Effect of Communication Mode on Disclosure of Nutrition Impact Symptoms During Nutrition Intervention Delivered to People With Upper Gastrointestinal Cancer.

Individuals diagnosed with upper gastrointestinal cancers experience a myriad of nutrition impact symptoms (NIS) compromise a person's ability to adequately meet their nutritional requirements leading to malnutrition, reduced quality of life and poorer survival. Electronic health (eHealth) is a potential strategy for improving the delivery of nutrition interventions by improving early and sustained access to dietitians to address both NIS and malnutrition. This study aimed to explore whether the mode of delivery affected participant disclosure of NIS during a nutrition intervention. Participants in the intervention groups received a nutrition intervention for 18 weeks from a dietitian via telephone or mobile application (app) using behaviour change techniques to assist in goal achievement. Poisson regression determined the proportion of individuals who reported NIS compared between groups. Univariate and multiple regression analyses of demographic variables explored the relationship between demographics and reporting of NIS. The incidence of reporting of NIS was more than 1.8 times higher in the telephone group (n = 38) compared to the mobile group (n = 36). Telephone predicted a higher likelihood of disclosure of self-reported symptoms of fatigue, nausea, and anorexia throughout the intervention period. A trusting therapeutic relationship built on human connection is fundamental and may not be achieved with current models of mobile health technologies.

Comparison of Goal Achievement during an Early, Intensive Nutrition Intervention Delivered to People with Upper Gastrointestinal Cancer by Telephone Compared with Mobile Application.

Objective: This study is aimed at exploring whether the mode of nutrition intervention delivery affected participant goal achievement in a three-arm randomised controlled trial of early and intensive nutrition intervention delivered to upper gastrointestinal cancer patients. Methods: Newly diagnosed upper gastrointestinal cancer patients were recruited from four tertiary hospitals in Melbourne, Australia. Participants in the intervention groups received a regular nutrition intervention for 18 weeks from an experienced dietitian via telephone or mobile application (app) using behaviour change techniques to assist in goal achievement. Univariate and multiple regression models using STATA determined goal achievement, dose, and frequency of contact between groups. A p value <0.05 was considered statistically significant. Results: The telephone group (n = 38) had 1.99 times greater frequency of contact with the research dietitian (95% CI: 1.67 to 2.36, p < 0.001) and 2.37 times higher frequency of goal achievement (95% CI: 1.1 to 5.11, p = 0.03) compared with the mobile app group (n = 36). The higher dose (RR 0.03) of intervention and more behaviour change techniques employed in the telephone group compared with the mobile app group increased participant goal achievement (95% CI: 0.01 to 0.04, p < 0.001). Discussion. Telephone nutrition intervention delivery led to a higher frequency of goal achievement compared to the mobile app intervention. There was also a higher number of behaviour change techniques employed which may have facilitated the greater goal achievement. Mobile app-based delivery may have poorer acceptance in this population with high levels of withdrawal. Practice Implications. We need to ensure that specifically designed technologies for our target populations are fit for purpose, efficacious, and acceptable to both patients and healthcare providers. This trial is registered with ACTRN12617000152325.

Relationship between circulating tumour DNA and skeletal muscle stores at diagnosis of pancreatic ductal adenocarcinoma: a cross-sectional study.

Low skeletal muscle index (SMI) and low skeletal muscle radiodensity (SMD) are associated with reduced survival time in pancreatic ductal adenocarcinoma (PDAC). The negative prognostic impact of low SMI and low SMD is often reported as independent of cancer stage when using traditional clinical staging tools. Therefore, this study sought to explore the relationship between a novel marker of tumour burden (circulating tumour DNA) and skeletal muscle abnormalities at diagnosis of PDAC. A retrospective cross-sectional study was conducted in patients who had plasma and tumour tissue samples stored in the Victorian Pancreatic Cancer Biobank (VPCB) at diagnosis of PDAC, between 2015 and 2020. Circulating tumour DNA (ctDNA) of patients with G12 and G13 KRAS mutations was detected and quantified. Pre-treatment SMI and SMD derived from analysis of diagnostic computed tomography imaging was tested for its association to presence and concentration of ctDNA, as well as conventional staging, and demographic variables. The study included 66 patients at PDAC diagnosis; 53% female, mean age 68.7 years (SD ± 10.9). Low SMI and low SMD were present in 69.7% and 62.1% of patients, respectively. Female gender was an independent risk factor for low SMI (OR 4.38, 95% CI 1.23-15.55, p = 0.022), and older age an independent risk factor for low SMD (OR 1.066, 95% CI 1.002-1.135, p = 0.044). No association between skeletal muscle stores and concentration of ctDNA (SMI r = - 0.163, p = 0.192; SMD r = 0.097, p = 0.438) or stage of disease according to conventional clinical staging [SMI F(3, 62) = 0.886, p = 0.453; SMD F(3, 62) = 0.717, p = 0.545] was observed. These results demonstrate that low SMI and low SMD are highly prevalent at diagnosis of PDAC, and suggest they are comorbidities of cancer rather than related to the clinical stage of disease. Future studies are needed to identify the mechanisms and risk factors for low SMI and low SMD at diagnosis of PDAC to aid screening and intervention development.

The roles of the dietitian in an 18-week telephone and mobile application nutrition intervention for upper gastrointestinal cancer: a qualitative analysis.

PURPOSE: This study aimed to explore the patient-dietitian experience during an 18-week nutrition counselling intervention delivered using the telephone and a mobile application to people newly diagnosed with upper gastrointestinal (UGI) cancer to (1) elucidate the roles of the dietitian during intervention delivery and (2) explore unmet needs impacting nutritional intake. METHODS: Qualitative case study methodology was followed, whereby the case was the 18-week nutrition counselling intervention. Dietary counselling conversations and post-intervention interviews were inductively coded from six case participants which included fifty-one telephone conversations (17 h), 244 written messages, and four interviews. Data were coded inductively, and themes constructed. The coding framework was subsequently applied to all post-study interviews (n = 20) to explore unmet needs. RESULTS: Themes describing the roles of the dietitian were as follows: regular collaborative problem-solving to encourage empowerment, a reassuring care navigator including anticipatory guidance, and rapport building via psychosocial support. Psychosocial support included provision of empathy, reliable care provision, and delivery of positive perspective. Despite intensive counselling from the dietitian, nutrition impact symptom management was a core unmet need as it required intervention beyond the scope of practice for the dietitian. CONCLUSION: Delivery of nutrition care via the telephone or an asynchronous mobile application to people with newly diagnosed UGI cancer required the dietitian to adopt a range of roles to influence nutritional intake: they empower people, act as care navigators, and provide psychosocial support. Limitations in dietitians' scope of practice identified unmet patient's needs in nutrition impact symptom management, which requires medication management. TRIAL REGISTRATION: 27th January 2017 Australian and New Zealand Clinical Trial Registry (ACTRN12617000152325).

Effect of Early and Intensive Telephone or Electronic Nutrition Counselling Delivered to People with Upper Gastrointestinal Cancer on Quality of Life: A Three-Arm Randomised Controlled Trial.

BACKGROUND: Delay in dietetic service provision for upper gastrointestinal cancer exacerbates disease-related malnutrition and consequently increases morbidity and mortality. Dietetic services are usually referral-based and provided face-to-face in inpatient or outpatient settings, which can delay the commencement of nutrition care. The aim of this study was to provide intensive dietetic intervention close to the time of diagnosis for upper gastrointestinal cancer and assess the effect on quality-adjusted life years. METHODS: A three-arm randomised controlled trial of adults newly diagnosed with upper gastrointestinal cancer was performed. A behavioural-based, individually tailored, symptom-directed nutrition intervention was provided in addition to usual care, delivered by a dietitian using a telephone (synchronously) or a mobile application (asynchronously) for 18 weeks, compared with a usual care control group. Data were collected at baseline, three, six, and twelve months post-randomisation. The primary outcome was quality-adjusted life years (EQ-5D-5L quality of life assessment tool). Data were analysed using linear mixed models. RESULTS: One hundred and eleven participants were randomised. Quality-adjusted life years were not different in the intervention groups compared with control (telephone: mean (95% CI) 0.04 (0.43, 2.3), p = 0.998; App: -0.08 (-0.18, 0.02), p = 0.135) after adjustment for baseline, nutrition risk status, age, and gender. Survival was similar between groups over 12 months. The asynchronous mobile app group had a greater number of withdrawals compared with the telephone group. CONCLUSION: Early and intensive nutrition counselling, delivered at home, during anticancer treatment did not change quality-adjusted life years or survival over 12 months compared with usual care. Behavioural counselling alone was unable to achieve nutritional adequacy. Dietetic services delivered asynchronously using a mobile app had low acceptance for patients undergoing anticancer treatment. TRIAL REGISTRATION: 27 January 2017 Australian and New Zealand Clinical Trial Registry, ACTRN12617000152325.

Association between skeletal muscle mass and quality of life in adults with cancer: a systematic review and meta-analysis.

Low skeletal muscle mass is known to be associated with poor morbidity and mortality outcomes in cancer, but evidence of its impact on health-related quality of life (HRQOL) is less established. This systematic review and meta-analysis was performed to investigate the relationship between skeletal muscle mass and HRQOL in adults with cancer. Five databases (Ovid MEDLINE, Embase via Ovid, CINAHL plus, Scopus, and PsycInfo) were systematically searched from 1 January 2007 until 2 September 2020. Studies reporting on the association between measures of skeletal muscle (mass and/or radiodensity) derived from analysis of computed tomography imaging, and a validated measure of HRQOL in adults with cancer, were considered for inclusion. Studies classifying skeletal muscle mass as a categorical variable (low or normal) were combined in a meta-analysis to investigate cross-sectional association with HRQOL. Studies reporting skeletal muscle as a continuous variable were qualitatively synthesized. A total of 14 studies involving 2776 participants were eligible for inclusion. Skeletal muscle mass classified as low or normal was used to dichotomize participants in 10 studies (n = 1375). Five different cut points were used for classification across the 10 studies, with low muscle mass attributed to 58% of participants. Low muscle mass was associated with poorer global HRQOL scores [n = 985 from seven studies, standardized mean difference -0.27, 95% confidence interval (CI) -0.40 to -0.14, P < 0.0001], and poorer physical functioning domain HRQOL scores (n = 507 from five studies, standardized mean difference -0.40, 95% CI -0.74 to -0.05, P = 0.02), but not social, role, emotional, or cognitive functioning domain scores (all P > 0.05). Five studies examined the cross-sectional relationship between HRQOL and skeletal muscle mass as a continuous variable and found little evidence of an association unless non-linear analysis was used. Two studies investigated the relationship between longitudinal changes in both skeletal muscle and HRQOL, reporting that an association exists across several HRQOL domains. Low muscle mass may be associated with lower global and physical functioning HRQOL scores in adults with cancer. The interpretation of this relationship is limited by the varied classification of low muscle mass between studies. There is a need for prospective, longitudinal studies examining the interplay between skeletal muscle mass and HRQOL over time, and data should be made accessible to enable reanalysis according to different cut points. Further research is needed to elucidate the causal pathways between these outcomes.

Impact of the Method of Delivering Electronic Health Behavior Change Interventions in Survivors of Cancer on Engagement, Health Behaviors, and Health Outcomes: Systematic Review and Meta-Analysis.

BACKGROUND: Increased accessibility to the internet and mobile devices has seen a rapid expansion in electronic health (eHealth) behavior change interventions delivered to patients with cancer and survivors using synchronous, asynchronous, and combined delivery methods. Characterizing effective delivery methods of eHealth interventions is required to enable improved design and implementation of evidence-based health behavior change interventions. OBJECTIVE: This study aims to systematically review the literature and synthesize evidence on the success of eHealth behavior change interventions in patients with cancer and survivors delivered by synchronous, asynchronous, or combined methods compared with a control group. Engagement with the intervention, behavior change, and health outcomes, including quality of life, fatigue, depression, and anxiety, were examined. METHODS: A search of Scopus, Ovid MEDLINE, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature Plus, PsycINFO, Cochrane CENTRAL, and PubMed was conducted for studies published between March 2007 and March 2019. We looked for randomized controlled trials (RCTs) examining interventions delivered to adult cancer survivors via eHealth methods with a measure of health behavior change. Random-effects meta-analysis was performed to examine whether the method of eHealth delivery impacted the level of engagement, behavior change, and health outcomes. RESULTS: A total of 24 RCTs were included predominantly examining dietary and physical activity behavior change interventions. There were 11 studies that used a synchronous approach and 11 studies that used an asynchronous approach, whereas 2 studies used a combined delivery method. Use of eHealth interventions improved exercise behavior (standardized mean difference [SMD] 0.34, 95% CI 0.21-0.48), diet behavior (SMD 0.44, 95% CI 0.18-0.70), fatigue (SMD 0.21, 95% CI -0.08 to 0.50; SMD change 0.22, 95% CI 0.09-0.35), anxiety (SMD 1.21, 95% CI: 0.36-2.07; SMD change 0.15, 95% CI -0.09 to 0.40), depression (SMD 0.15, 95% CI 0.00-0.30), and quality of life (SMD 0.12, 95% CI -0.10 to 0.34; SMD change 0.14, 95% CI 0.04-0.24). The mode of delivery did not influence the amount of dietary and physical activity behavior change observed. CONCLUSIONS: Physical activity and dietary behavior change eHealth interventions delivered to patients with cancer or survivors have a small to moderate impact on behavior change and a small to very small benefit to quality of life, fatigue, depression, and anxiety. There is insufficient evidence to determine whether asynchronous or synchronous delivery modes yield superior results. Three-arm RCTs comparing delivery modes with a control with robust engagement reporting are required to determine the most successful delivery method for promoting behavior change and ultimately favorable health outcomes.

A process and mechanism of action evaluation of the effect of early and intensive nutrition care, delivered via telephone or mobile application, on quality of life in people with upper gastrointestinal cancer: a study protocol.

BACKGROUND: Cancers of the upper gastrointestinal tract commonly result in malnutrition, which increases morbidity and mortality. Current nutrition best practice lacks a mechanism to provide early and intensive nutrition support to these patients. A 3-arm parallel randomised controlled trial is testing the provision of a tailored, nutritional counselling intervention delivered using a synchronous, telephone-based approach or an asynchronous, mobile application-based approach to address this problem. This protocol outlines the design and methods that will be used to undertake an evaluation of the implementation process, which is imperative for successful replication and dissemination. METHODS: A concurrent triangulation mixed methods comparative analysis will be undertaken. The nutrition intervention will be provided using best practice behaviour change techniques and communicated either via telephone or via mHealth. The implementation outcomes that will be measured are: fidelity to the nutrition intervention protocol and to the delivery approach; engagement; acceptability and contextual factors. Qualitative data from recorded telephone consultations and written messages will be analysed through a coding matrix against the behaviour change techniques outlined in the standard operating procedure, and also thematically to determine barriers and enablers. Negative binomial regression will be used to test for predictive relationships between intervention components with health-related quality of life and nutrition outcomes. Post-intervention interviews with participants and health professionals will be thematically analysed to determine the acceptability of delivery approaches. NVivo 11 Pro software will be used to code for thematic analysis. STATA version 15 will be used to perform quantitative analysis. DISCUSSION: The findings of this process evaluation will provide evidence of the core active ingredients that enable the implementation of best practice nutrition intervention for people with upper gastrointestinal cancer. Elucidation of the causal pathways of successful implementation and the important relationship to contextual delivery are anticipated. With this information, a strategy for sustained implementation across broader settings will be developed which impact the quality of life and nutritional status of individuals with upper gastrointestinal cancer. TRIAL REGISTRATION: 27th January 2017 Australian and New Zealand Clinical Trial Registry ( ACTRN12617000152325 ).

Effect of early and intensive nutrition care, delivered via telephone or mobile application, on quality of life in people with upper gastrointestinal cancer: study protocol of a randomised controlled trial.

BACKGROUND: A major challenge for those living with cancers of the upper gastrointestinal tract (oesophagus, stomach and pancreas), is the impact of the disease and treatment on nutritional status and quality of life. People with cancer and malnutrition have a greater risk of morbidity and mortality. Nutrition intervention is recommended to commence immediately in those who are malnourished or at risk of malnutrition. Novel cost-effective approaches that can deliver early, pre-hospital nutrition intervention before usual hospital dietetic service is commenced are needed. Linking clinicians and patients via mobile health (mHealth) and wireless technologies is a contemporary solution not yet tested for delivery of nutrition therapy to people with cancer. The aim of this study is to commence nutrition intervention earlier than usual care and evaluate the effects of using the telephone or mHealth for intervention delivery. It is hypothesised that participants allocated to receive the early and intensive pre-hospital dietetic service will have more quality-adjusted life years lived compared with control participants. This study will also demonstrate the feasibility and effectiveness of mHealth for the nutrition management of patients at home undergoing cancer treatment. METHODS: This study is a prospective three-group randomised controlled trial, with a concurrent economic evaluation. The 18 week intervention is provided in addition to usual care and is delivered by two different modes, via telephone (group 1) or via mHealth (group 2), The control group receives usual care alone (group 3). The intervention is an individually tailored, symptom-directed nutritional behavioural management program led by a dietitian. Participants will have at least fortnightly reviews. The primary outcome is quality adjusted life years lived and secondary outcomes include markers of nutritional status. Outcomes will be measured at three, six and 12 months follow up. DISCUSSION: The findings will provide evidence of a strategy to implement early and intensive nutrition intervention outside the hospital setting that can favourably impact on quality of life and nutritional status. This patient-centred approach is relevant to current health service provision and challenges the current reactive delivery model of care. TRIAL REGISTRATION: 27th January 2017 Australian and New Zealand Clinical Trial Registry ( ACTRN12617000152325 ).

Long-term follow-up of the potential benefits of early nutritional intervention in adults with upper gastrointestinal cancer: a pilot randomised trial.

PURPOSE: This study aimed to evaluate the long-term survival of all patients who participated in a pilot randomised trial of an early nutritional intervention for adults with upper gastrointestinal cancer. It also sought to identify factors that predicted patient mortality. METHODS: All participants (n = 21) who were randomised into the original study were followed for a maximum of 5 years and 2 months (final follow-up April 2016). The primary outcome measure was time from date of recruitment until date of death, ascertained by the Victorian Cancer Registry and/or Monash Health Scanned Medical Records. Secondary analyses were conducted to identify factors that adversely affected survival. RESULTS: At the end of the follow-up period, three patients were alive in the nutrition intervention group whilst only two patients were living from the standard care group. Visual evaluation of the Kaplan-Meier survival curves demonstrated a possible survival benefit from being exposed to the intervention between 6 months and 1.4 years post-recruitment, though this benefit dissipated soon after. The intervention was not associated with increased survival in univariate analyses, but was after adjustment for other factors found to adversely impact on survival (adjusted hazard ratio 0.12 (95% CI 0.02-0.72) p = 0.02). These factors were being a smoker (14.2 (1.43 to 140.67), p = 0.02); low baseline physical functioning (1.11 (1.01 to 1.21), p = 0.03); high baseline fatigue (1.09 (1.02-1.16), p = 0.007); and high baseline dyspnoea (1.08 (1.02-1.13), p = 0.003). CONCLUSION: Early and intensive nutrition intervention may increase the survival of people with upper gastrointestinal cancer.

Potential benefits of early nutritional intervention in adults with upper gastrointestinal cancer: a pilot randomised trial.

PURPOSE: This study aimed to test whether a very early nutrition intervention delivered over the telephone was feasible and could improve outcomes amongst patients with upper gastrointestinal cancer. METHODS: Participants with a histologically proven new diagnosis of primary oesophageal or stomach cancer and who were to undergo surgery and/or chemotherapy were randomised to receive either standard nutrition care (SC) or early and intensive nutrition intervention (NI) over the telephone/face-to-face. Participants were followed for 6 months. The primary outcome was quality of life (QoL), assessed using the European Organization for Research and Treatment of Cancer Global Quality of Life questionnaire C30 (EORTC QLQ-C30) and the European Quality of Life Instrument (EQ-5D) tool; secondary outcomes were nutritional status and survival. RESULTS: Twenty-one participants were recruited (11 SC and 10 NI). At baseline, the prevalence of malnutrition was 90 %. Compared with SC, the NI group had a significantly higher EORTC global QoL score at the first mid-study follow-up (coefficient (95 % CI) 21.0 (12.1, 29.9) adjusted for baseline, p < 0.001) and at 26 weeks (28.4 (21.3, 35.4) adjusted for baseline, p < 0.001). Nutritional risk score was lower (p < 0.001), and loss of body weight attenuated (p < 0.001) in the NI group compared with SC. Six deaths occurred during the study, five in the SC group and one in the NI group (p = 0.06). The mean time spent with a dietitian per contact was significantly less for the NI group compared with SC (16(3) vs 40(6) min per dietetic contact, p < 0.001). CONCLUSIONS: This pilot study has shown the potential of a novel telephone-based early and intensive dietetic model of care for newly diagnosed upper gastrointestinal cancer patients.

Evaluating RNA preparation options for archived myocardial biopsies.

High quality RNA is the key to producing meaningful gene expression analyses. Human cardiac tissue specimens are extremely valuable, but may not always be obtained under optimal conditions and are frequently fibrotic. We provide a practical guide to assist in assessing the efficacy of two different RNA extraction methods applied to these challenging specimens. We describe how to compare 'single-step' and 'multi-step' extraction processes and discuss how to interpret information available through microfluidic and spectroscopic analyses to evaluate sample quality.

Dietary fish oil is antihypertrophic but does not enhance postischemic myocardial function in female mice.

Clinically and experimentally, a case for omega-3 polyunsaturated fatty acid (PUFA) cardioprotection in females has not been clearly established. The goal of this study was to investigate whether dietary omega-3 PUFA supplementation could provide ischemic protection in female mice with an underlying genetic predisposition to cardiac hypertrophy. Mature female transgenic mice (TG) with cardiac-specific overexpression of angiotensinogen that develop normotensive cardiac hypertrophy and littermate wild-type (WT) mice were fed a fish oil-derived diet (FO) or PUFA-matched control diet (CTR) for 4 wk. Myocardial membrane lipids, ex vivo cardiac performance (intraventricular balloon) after global no-flow ischemia and reperfusion (15/30 min), and reperfusion arrhythmia incidence were assessed. FO diet suppressed cardiac growth by 5% and 10% in WT and TG, respectively (P < 0.001). The extent of mechanical recovery [rate-pressure product (RPP) = beats/min x mmHg] of FO-fed WT and TG hearts was similar (50 +/- 7% vs. 45 +/- 12%, 30 min reperfusion), and this was not significantly different from CTR-fed WT or TG. To evaluate whether systemic estrogen was masking a protective effect of the FO diet, the responses of ovariectomized (OVX) WT and TG mice to FO dietary intervention were assessed. The extent of mechanical recovery of FO-fed OVX WT and TG (RPP, 50 +/- 4% vs. 64 +/- 8%) was not enhanced compared with CTR-fed mice (RPP, 60 +/- 11% vs. 80 +/- 8%, P = 0.335). Dietary FO did not suppress the incidence of reperfusion arrhythmias in WT or TG hearts (ovary-intact mice or OVX). Our findings indicate a lack of cardioprotective effect of dietary FO in females, determined by assessment of mechanical and arrhythmic activity postischemia in a murine ex vivo heart model.

The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy.

Important sex differences in cardiovascular disease outcomes exist, including conditions of hypertrophic cardiomyopathy and cardiac ischemia. Studies of sex differences in the extent to which load-independent (primary) hypertrophy modulates the response to ischemia-reperfusion (I/R) damage have not been characterized. We have previously described a model of primary genetic cardiac hypertrophy, the hypertrophic heart rat (HHR). In this study the sex differences in HHR cardiac function and responses to I/R [compared to control normal heart rat (NHR)] were investigated ex vivo. The ventricular weight index was markedly increased in HHR female (7.82 +/- 0.49 vs. 4.80 +/- 0.10 mg/g; P < 0.05) and male (5.76 +/- 0.22 vs. 4.62 +/- 0.07 mg/g; P < 0.05) hearts. Female hearts of both strains exhibited a reduced basal contractility compared with strain-matched males [maximum first derivative of pressure (dP/dt(max)): NHR, 4,036 +/- 171 vs. 4,258 +/- 152 mmHg/s; and HHR, 3,974 +/- 160 vs. 4,540 +/- 259 mmHg/s; P < 0.05]. HHR hearts were more susceptible to I/R (I = 25 min, and R = 30 min) injury than NHR hearts (decreased functional recovery, and increased lactate dehydrogenase efflux). Female NHR hearts exhibited a significantly greater recovery (dP/dt(max)) post-I/R relative to male NHR (95.0 +/- 12.2% vs. 60.5 +/- 9.4%), a resistance to postischemic dysfunction not evident in female HHR (29.0 +/- 5.6% vs. 25.9 +/- 6.3%). Ventricular fibrillation was suppressed, and expression levels of Akt and ERK1/2 were selectively elevated in female NHR hearts. Thus the occurrence of load-independent primary cardiac hypertrophy undermines the intrinsic resistance of female hearts to I/R insult, with the observed abrogation of endogenous cardioprotective signaling pathways consistent with a potential mechanistic role in this loss of protection.