Scott A. Grandy

Overexpression of type 1 angiotensin II receptors impairs excitation-contraction coupling in the mouse heart

Transgenic mice that overexpress human type 1 angiotensin II receptor (AT(1)R) in the heart develop cardiac hypertrophy. Previously, we have shown that in 6-mo AT(1)R mice, which exhibit significant cardiac remodeling, fractional shortening is decreased. However, it is not clear whether altered contractility is attributable to AT(1)R overexpression or is secondary to cardiac hypertrophy/remodeling. Thus the present study characterized the effects of AT(1)R overexpression on ventricular L-type Ca(2+) currents (I(CaL)), cell shortening, and Ca(2+) handling in 50-day and 6-mo-old male AT(1)R mice. Echocardiography showed there was no evidence of cardiac hypertrophy in 50-day AT(1)R mice but that fractional shortening was decreased. Cellular experiments showed that cell shortening, I(CaL), and Ca(v)1.2 mRNA expression were significantly reduced in 50-day and 6-mo-old AT(1)R mice compared with controls. In addition, Ca(2+) transients and caffeine-induced Ca(2+) transients were reduced whereas the time to 90% Ca(2+) transient decay was prolonged in both age groups of AT(1)R mice. Western blot analysis revealed that sarcoplasmic reticulum Ca(2+)-ATPase and Na(+)/Ca(2+) exchanger protein expression was significantly decreased in 50-day and 6-mo AT(1)R mice. Overall, the data show that cardiac contractility and the mechanisms that underlie excitation-contraction coupling are altered in AT(1)R mice. Furthermore, since the alterations in contractility occur before the development of cardiac hypertrophy, it is likely that these changes are attributable to the increased activity of the renin-angiotensin system brought about by AT(1)R overexpression. Thus it is possible that AT(1)R blockade may help maintain cardiac contractility in individuals with heart disease.

Moderate Exercise Has Limited but Distinguishable Effects on the Mouse Microbiome

The bacteria that live in our gut have a complex yet vital relationship with our health. Environmental factors that influence the gut microbiome are of great interest, as recent research demonstrates that these microbes, mostly bacteria, are important for normal host physiology. Diseases such as obesity, diabetes, inflammatory bowel disease, and colon cancer have also been linked to shifts in the microbiome. Exercise is known to have beneficial effects on these diseases; however, much less is known about its direct impact on the gut microbiome. Our results illustrate that exercise has a moderate but measurable effect on gut microbial communities in mice. These methods can be used to provide important insight into other factors affecting the microbiome and our health. ABSTRACT The gut microbiome is known to have a complex yet vital relationship with host health. While both exercise and the gut microbiome have been shown to impact human health independently, the direct effects of moderate exercise on the intestinal microbiota remain unclear. In this study, we compared gut microbial diversity and changes in inflammatory markers associated with exercise over an 8-week period in mice that performed either voluntary exercise (VE) (n = 10) or moderate forced exercise (FE) (n = 11) and mice that did not perform any exercise (n = 21). VE mice, but not FE mice, had increased food intake and lean body mass compared to sedentary mice. The levels of inflammatory markers associated with exercise were similar for mice in all three groups. Traditional microbial profiles comparing operational taxonomic units (OTUs) in samples (P > 0.1) and multivariate analysis of beta diversity via Adonis testing (P > 0.1) did not identify significantly altered taxonomic profiles in the voluntary or forced exercise group compared to the sedentary controls. However, a random forests machine learning model, which takes into account the relationships between bacteria in a community, classified voluntary exercisers and nonexercisers with 97% accuracy at 8 weeks. The top bacteria used by the model allowed us to identify known taxa (Bacteroides, S24-7, and Lactobacillus) and novel taxa (Rikenellaceae and Lachnospiraceae) associated with exercise. Although aerobic exercise in mice did not result in significant changes of abundance in gut microbes or in host inflammatory response, more sophisticated computational methods could identify some microbial shifts. More study is needed on the effects of various exercise intensities and their impact on the gut microbiome. IMPORTANCE The bacteria that live in our gut have a complex yet vital relationship with our health. Environmental factors that influence the gut microbiome are of great interest, as recent research demonstrates that these microbes, mostly bacteria, are important for normal host physiology. Diseases such as obesity, diabetes, inflammatory bowel disease, and colon cancer have also been linked to shifts in the microbiome. Exercise is known to have beneficial effects on these diseases; however, much less is known about its direct impact on the gut microbiome. Our results illustrate that exercise has a moderate but measurable effect on gut microbial communities in mice. These methods can be used to provide important insight into other factors affecting the microbiome and our health.

Association between Diet Quality and Adiposity in the Atlantic PATH Cohort

The aim of this study was to examine diet quality among participants in the Atlantic Partnership for Tomorrow’s Health (PATH) cohort and to assess the association with adiposity. Data were collected from participants (n = 23,768) aged 35–69 years that were residents of the Atlantic Canadian provinces. Both measured and self-reported data were used to examine adiposity (including body mass index (BMI), abdominal obesity, waist-to-hip ratio and fat mass) and food frequency questionnaires were used to assess diet quality. Overall, diet quality was statistically different among provinces. Of concern, participants across all the provinces reported consuming only 1–2 servings of vegetables and 1–2 servings fruit per day. However, participants also reported some healthy dietary choices such as consuming more servings of whole grains than refined grains, and eating at fast food restaurants ≤1 per month. Significant differences in BMI, body weight, percentage body fat, and fat mass index were also observed among provinces. Adiposity measures were positively associated with consumption of meat/poultry, fish, snack food, sweeteners, diet soft drinks, and frequenting fast food restaurants, and inversely associated with consumption of whole grains and green tea. Although all four provinces are in the Atlantic region, diet quality vary greatly among provinces and are associated with adiposity.

Protein kinase A-mediated phosphorylation contributes to enhanced contraction observed in mice that overexpress beta-adrenergic receptor kinase-1.

Transgenic mice with cardiac specific overexpression of β-adrenergic receptor kinase-1 (βARK-1) exhibit reduced contractility in the presence of adrenergic stimulation. However, whether contractility is altered in the absence of exogenous agonist is not clear. Effects of βARK-1 overexpression on contraction were examined in mouse ventricular myocytes, studied at 37°C, in the absence of adrenergic stimulation. In myocytes voltage-clamped with microelectrodes (18–26 MΩ; 2.7 M KCl) to minimize intracellular dialysis, contractions were significantly larger in βARK-1 cells than in wild-type myocytes. In contrast, when cells were dialyzed with patch pipette solution (1–3 MΩ; 0 mM NaCl, 70 mM KCl, 70 mM potassium aspartate, 4 mM MgATP, 1 mM MgCl2, 2.5 mM KH2PO4, 0.12 mM CaCl2, 0.5 mM EGTA, and 10 mM HEPES), the extent of cell shortening was similar in wild-type and βARK-1 myocytes. Furthermore, when cells were dialyzed with solutions that contained phosphodiesterase-sensitive sodium-cAMP (50 μM), the extent of cell shortening was similar in wild-type and βARK-1 myocytes. However, when patch solutions were supplemented with phosphodiesterase-resistant 8-bromo-cAMP (50 μM), contractions were larger in βARK-1 than wild-type cells. This difference was eliminated by the protein kinase A inhibitor N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89). Interestingly, Ca2+ current amplitudes and inactivation rates were similar in βARK-1 and wild-type cells in all experiments. These results suggest components of the adenylyl cyclase-protein kinase A pathway are sensitized by chronically increased βARK-1 activity, which may augment contractile function in the absence of exogenous agonist. Thus, changes in contractile function in myocytes from failing hearts may reflect, in part, effects of chronic up-regulation of βARK-1 on the cAMP-protein kinase A pathway.

Fruit and vegetable intake and body adiposity among populations in Eastern Canada: the Atlantic Partnership for Tomorrow’s Health Study

Objectives The prevalence of obesity among populations in the Atlantic provinces is the highest in Canada. Some studies suggest that adequate fruit and vegetable consumption may help body weight management. We assessed the associations between fruit and vegetable intake with body adiposity among individuals who participated in the baseline survey of the Atlantic Partnership for Tomorrow’s Health (Atlantic PATH) cohort study. Methods We carried out a cross-sectional analysis among 26 340 individuals (7979 men and 18 361 women) aged 35–69 years who were recruited in the baseline survey of the Atlantic PATH study. Data on fruit and vegetable intake, sociodemographic and behavioural factors, chronic disease, anthropometric measurements and body composition were included in the analysis. Results In the multivariable regression analyses, 1 SD increment of total fruit and vegetable intake was inversely associated with body mass index (−0.12 kg/m2; 95% CI −0.19 to –0.05), waist circumference (−0.40 cm; 95% CI −0.58 to –0.23), percentage fat mass (−0.30%; 95% CI −0.44 to –0.17) and fat mass index (−0.14 kg/m2; 95% CI −0.19 to –0.08). Fruit intake, but not vegetable intake, was consistently inversely associated with anthropometric indices, fat mass, obesity and abdominal obesity. Conclusions Fruit and vegetable consumption was inversely associated with body adiposity among the participant population in Atlantic Canada. This association was primarily attributable to fruit intake. Longitudinal studies and randomised trials are warranted to confirm these observations and investigate the underlying mechanisms.

Multimorbidity in Atlantic Canada and association with low levels of physical activity

Owing to an aging population and medical advances, the anticipated growth and prevalence of multimorbidity has been recognized as a significant challenge and priority in health care settings. Although physical activity has been shown to play a vital role in the primary and secondary prevention of chronic disease, much less is known about the relationship between physical activity and multimorbidity. The objective of the present study was to examine the relationship between physical activity levels and multimorbidity in male and female adults after adjusting for key demographic, geographical, and lifestyle factors. The study drew data from a prospective cohort in Atlantic Canada (2009-2015). The sample included 18,709 participants between the ages of 35-69. Eighteen chronic diseases were identified. Physical activity levels were estimated based on the long form of the International Physical Activity Questionnaire. Using logistic regression analysis, we found that multimorbid individuals were significantly more likely to be physically inactive (OR=1.26; 95% CI 1.10, 1.44) after adjusting for key sociodemographic and lifestyle characteristics. Additional stratified analyses suggest that the magnitude of the effect between multimorbidity and physical activity was stronger for men (OR=1.41; 95% CI 1.12, 1.79) than women (OR=1.18; CI 1.00, 1.39) and those living in rural (OR=1.43; CI 1.10, 1.85) versus urban (OR=1.20; CI 1.02, 141) areas. Given the generally low levels of physical activity across populations and a growing prevalence of multimorbidity, there is a need for a prospective study to explore causal associations between physical activity, multimorbidity, and health outcomes.

Aerobic exercise and cardiopulmonary fitness in childhood cancer survivors treated with a cardiotoxic agent: a meta-analysis

PurposeThe main purpose of this review was to synthesize evidence from existing childhood cancer survivor studies that report the effect of aerobic exercise on cardiopulmonary fitness (a marker of cardiovascular health), in survivors that were currently receiving or had been treated with a cardiotoxic agent.MethodsStudies were identified for this review by searching both electronic databases of peer-reviewed articles, as well as various sources of gray literature. Risk of bias was qualitatively assessed in these studies using the domains outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Data was analyzed quantitatively using random-effects meta-analyses and subgroup analyses in RevMan Software.ResultsMeta-analysis of pooled evidence from the nine included studies suggests that aerobic exercise has a statistically and clinically significant positive effect on cardiopulmonary fitness (effect estimate = 6.92%, p value = 0.02). Findings from subgroup analyses of clinical characteristics and exercise parameters were not significant.ConclusionsThe findings from this review, although not directly demonstrating a cardioprotective effect, are a preliminary step towards establishing the putative cardioprotective effect of aerobic exercise against the direct cardiotoxic impact of cancer treatments. The significant positive effect estimate in favor of aerobic exercise is a small but important advancement towards the standardization of aerobic exercise in childhood cancer survivors. Further studies are necessary.

1288 The effect of shift work on cardiometabolic health: findings from the atlantic path cohort study

Introduction Contemporary work environments increasingly rely upon a 24 hour work cycle resulting in more employees exposed to shift work. 30% of working age Canadians work evening, night and rotating shifts, and 21% of workers in the European Union. Compared to regular daytime work, shift work has the potential for disturbing sleep patterns and disrupting circadian rhythms with adverse health effects. Methods Participation was limited to volunteers from the Atlantic Canadian Provinces (Nova Scotia, New Brunswick, Newfoundland and Labrador, and Prince Edward Island). 12 413 participants, including 4155 shift workers and 8258 non-shift workers (matched 1:2 by age, sex, and education) from the Atlantic Partnership for Tomorrow’s Health (PATH) study. Multiple general linear and logistic regression models were used to assess differences in body adiposity and self-reported cardiometabolic disease outcomes between shift workers and non-shift workers. Results There was a significant increased risk of obesity and diabetes among shift workers compared to their matched controls. Shift workers were 18% more likely to be obese (95% CI: 9 to 29) and 8% more likely to have abdominal obesity (95% CI: 0 to 17). Shift workers were 31% more likely to have diabetes than non-shift workers (95% CI: 11 to 56). The strength of this association was further demonstrated by controlling for participants’ fat mass index (FMI), which resulted in a 28% increased risk of diabetes among shift workers (95% CI: 2 to 60). Despite the increased likelihood of being physically active, regular night shift workers had higher levels of BMI, waist circumference, and fat mass compared with matched controls. Conclusion Despite higher levels of physical activity and lower levels of sedentary behaviour, shift workers were more likely to have increased rates of diabetes and obesity and are subsequently at increased the risk of developing other chronic disease. The effects of shift work on cardiometabolic status may be independent of simple obesity.

Correction: DeClercq, V.; et al. Association between Diet Quality and Adiposity in the Atlantic PATH Cohort. Nutrients 2017, 9, 1155

The authors request the following corrections to their paper [1]. [...].

Chronic Treatment With the ACE Inhibitor Enalapril Attenuates the Development of Frailty and Differentially Modifies Pro- and Anti-inflammatory Cytokines in Aging Male and Female C57BL/6 Mice

Studies on interventions that can delay or treat frailty in humans are limited. There is evidence of beneficial effects of angiotensin converting enzyme (ACE) inhibitors on aspects related to frailty, such as physical function, even in those without cardiovascular disease. This study aimed to longitudinally investigate the effect of an ACE inhibitor on frailty in aging male and female mice. Frailty was assessed with a clinical frailty index (FI) which quantifies health-related deficits in middle-aged (9-13 months) and older (16-25 months) mice. Chronic treatment with enalapril (30 mg/kg/day in feed) attenuated frailty in middle-aged and older female mice, and older male mice, without a long-term effect on blood pressure. Enalapril treatment resulted in a reduction in the pro-inflammatory cytokines interleukin (IL)-1α, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1a in older female mice, and an increase in the anti-inflammatory cytokine IL-10 in older male mice compared to control animals. These sex-specific effects on inflammation may contribute to the protective effects of enalapril against frailty. This is the first study to examine the longitudinal effect of an intervention on the FI in mice, and provides pre-clinical evidence that enalapril may delay the onset of frailty, even when started later in life.