Andrew N. Stammers

The regulation of sarco(endo)plasmic reticulum calcium-ATPases (SERCA).

The sarco(endo)plasmic reticulum calcium ATPase (SERCA) is responsible for transporting calcium (Ca(2+)) from the cytosol into the lumen of the sarcoplasmic reticulum (SR) following muscular contraction. The Ca(2+) sequestering activity of SERCA facilitates muscular relaxation in both cardiac and skeletal muscle. There are more than 10 distinct isoforms of SERCA expressed in different tissues. SERCA2a is the primary isoform expressed in cardiac tissue, whereas SERCA1a is the predominant isoform expressed in fast-twitch skeletal muscle. The Ca(2+) sequestering activity of SERCA is regulated at the level of protein content and is further modified by the endogenous proteins phospholamban (PLN) and sarcolipin (SLN). Additionally, several novel mechanisms, including post-translational modifications and microRNAs (miRNAs) are emerging as integral regulators of Ca(2+) transport activity. These regulatory mechanisms are clinically relevant, as dysregulated SERCA function has been implicated in the pathology of several disease states, including heart failure. Currently, several clinical trials are underway that utilize novel therapeutic approaches to restore SERCA2a activity in humans. The purpose of this review is to examine the regulatory mechanisms of the SERCA pump, with a particular emphasis on the influence of exercise in preventing the pathological conditions associated with impaired SERCA function.

Protocol for the PREHAB study—Pre-operative Rehabilitation for reduction of Hospitalization After coronary Bypass and valvular surgery: a randomised controlled trial

Introduction Frailty is a geriatric syndrome characterised by reductions in muscle mass, strength, endurance and activity level. The frailty syndrome, prevalent in 25–50% of patients undergoing cardiac surgery, is associated with increased rates of mortality and major morbidity as well as function decline postoperatively. This trial will compare a preoperative, interdisciplinary exercise and health promotion intervention to current standard of care (StanC) for elective coronary artery bypass and valvular surgery patients for the purpose of determining if the intervention improves 3-month and 12-month clinical outcomes among a population of frail patients waiting for elective cardiac surgery. Methods and analysis This is a multicentre, randomised, open end point, controlled trial using assessor blinding and intent-to-treat analysis. Two-hundred and forty-four elective cardiac surgical patients will be recruited and randomised to receive either StanC or StanC plus an 8-week exercise and education intervention at a certified medical fitness facility. Patients will attend two weekly sessions and aerobic exercise will be prescribed at 40–60% of heart rate reserve. Data collection will occur at baseline, 1–2 weeks preoperatively, and at 3 and 12 months postoperatively. The primary outcome of the trial will be the proportion of patients requiring a hospital length of stay greater than 7 days. Potential impact of study The healthcare team is faced with an increasingly complex older adult patient population. As such, this trial aims to provide novel evidence supporting a health intervention to ensure that frail, older adult patients thrive after undergoing cardiac surgery. Ethics and dissemination Trial results will be published in peer-reviewed journals, and presented at national and international scientific meetings. The University of Manitoba Health Research Ethics Board has approved the study protocol V.1.3, dated 11 August 2014 (H2014:208). Trial registration number The trial has been registered on ClinicalTrials.gov, a registry and results database of privately and publicly funded clinical studies (NCT02219815).

The impact of frailty on functional survival in patients 1 year after cardiac surgery

Objective: This study determined whether frailty provides incremental value to the European System for Cardiac Operative Risk Evaluation II in identifying patients at risk of poor 1‐year functional survival. Methods: This prospective study in patients undergoing cardiac surgery defined frailty using 3 common definitions: (1) the Modified Fried Criteria; (2) the Short Physical Performance Battery; and (3) the Clinical Frailty Scale. The primary outcome was functional survival, defined as being alive at 1 year postsurgery with a health‐related quality of life score greater than 60 on the EuroQol‐Visual Analogue Scale. Results: Of the 188 participants, 49.5%, 52.6%, and 31.9% were deemed frail according to the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale, respectively. The median age of our cohort was 71.0 years (29.3% female). The probability of functional survival at 1 year for the entire cohort was 73.9%. After adjusting for the European System for Cardiac Operative Risk Evaluation II, patients deemed frail under the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale had an increased odds ratio for poor functional survival of 3.44, 3.47, and 2.08, respectively. When compared with the European System for Cardiac Operative Risk Evaluation II alone, the Modified Fried Criteria, Short Physical Performance Battery, and Clinical Frailty Scale showed an absolute improvement in the discrimination slope of 6.7%, 6.5%, and 2.4% with a category‐free classification improvement of 59.6%, 59.2%, and 35.1%, respectively. Conclusions: Preoperative frailty was associated with a 2‐ to 3.5‐fold higher risk of poor functional survival 1 year after cardiac surgery. The addition of frailty to the European System for Cardiac Operative Risk Evaluation II provides incremental value in identifying patients at risk of poor functional survival 1 year postsurgery, regardless of frailty definition.

Differential regulation of the fiber type-specific gene expression of the sarcoplasmic reticulum calcium-ATPase isoforms induced by exercise training

The regulatory role of adenosine monophosphate-activated protein kinase (AMPK)-α2 on sarcoplasmic reticulum calcium-ATPase (SERCA) 1a and SERCA2a in different skeletal muscle fiber types has yet to be elucidated. Sedentary (Sed) or exercise-trained (Ex) wild-type (WT) and AMPKα2-kinase dead (KD) transgenic mice, which overexpress a mutated and inactivated AMPKα2 subunit, were utilized to characterize how genotype or exercise training influenced the regulation of SERCA isoforms in gastrocnemius. As expected, both Sed and Ex KD mice had >40% lower AMPK phosphorylation and 30% lower SERCA1a protein than WT mice (P < 0.05). In contrast, SERCA2a protein was not different among KD and WT mice. Exercise increased SERCA1a and SERCA2a protein content among WT and KD mice, compared with their Sed counterparts. Maximal SERCA activity was lower in KD mice, compared with WT. Total phospholamban protein was higher in KD mice than in WT and lower in Ex compared with Sed mice. Exercise training increased phospholamban Ser(16) phosphorylation in WT mice. Laser capture microdissection and quantitative PCR indicated that SERCA1a mRNA expression among type I fibers was not altered by genotype or exercise, but SERCA2a mRNA was increased 30-fold in WT+Ex, compared with WT+Sed. In contrast, the exercise-stimulated increase for SERCA2a mRNA was blunted in KD mice. Exercise upregulated SERCA1a and SERCA2a mRNA among type II fibers, but was not altered by genotype. Collectively, these data suggest that exercise differentially influences SERCA isoform expression in type I and type II fibers. Additionally, AMPKα2 influences the regulation of SERCA2a mRNA in type I skeletal muscle fibers following exercise training.

Prevalence of frailty in Canadians 18–79 years old in the Canadian Health Measures Survey

BackgroundThere is little certainty as to the prevalence of frailty in Canadians in younger adulthood. This study examines and compares the prevalence of frailty in Canadians 18–79 years old using the Accumulation of Deficits and Fried models of frailty.MethodsThe Canadian Health Measures Study data were used to estimate the prevalence of frailty in adults 18–79 years old. A 23-item Frailty Index using the Accumulation of Deficits Model (cycles 1–3; n = 10,995) was developed; frailty was defined as having the presence of 25% or more indices, including symptoms, chronic conditions, and laboratory variables. Fried frailty (cycles 1–2; n = 7,353) included the presence of ≥3 criteria: exhaustion, physical inactivity, poor mobility, unintentional weight loss, and poor grip strength.ResultsThe prevalence of frailty was 8.6 and 6.6% with the Accumulation of Deficits and the Fried Model. Comparing the Fried vs. the Accumulation of Deficits Model, the prevalence of frailty was 5.3% vs. 1.8% in the 18–34 age group, 5.7% vs. 4.3% in the 35–49 age group, 6.9% vs. 11.6% in the 50–64 age group, and 7.8% vs. 20.2% in the 65+ age group. Some indices were higher in the younger age groups, including persistent cough, poor health compared to a year ago, and asthma for the accumulation of deficits model, and exhaustion, unintentional weight loss, and weak grip strength for the Fried model, compared to the older age groups.ConclusionsThese data show that frailty is prevalent in younger adults, but varies depending on which frailty tool is used. Further research is needed to determine the health impact of frailty in younger adults.

Cardiovascular complications of type 2 diabetes in youth.

The prevalence of type 2 diabetes mellitus (T2DM) in youth has increased dramatically over the past decades. The literature also suggests that the progression from an impaired glucose tolerance state to established T2DM is more rapid in youth, compared to adults. The presence of significant cardiovascular complications in youth with T2DM, including cardiac, macrovascular, and microvascular remodeling, is another major issue in this younger cohort and poses a significant threat to the healthcare system. However, this issue is only now emerging as a major public health concern, with few data to support optimal treatment targets and strategies to reduce cardiovascular disease (CVD) risk in youth with T2DM. Accordingly, the purpose of this minireview is to better understand the cardiovascular complications in youth with T2DM. We briefly describe the pathophysiology from youth studies, including oxidative stress, inflammation, renin-angiotensin aldosterone system, and epigenetics, which link T2DM and CVD. We also describe the literature concerning the early signs of CVD in youth and potential treatment options to reduce cardiovascular risk.

Systematic review of preoperative physical activity and its impact on postcardiac surgical outcomes

Objectives The objective of this systematic review was to study the impact of preoperative physical activity levels on adult cardiac surgical patients’ postoperative: (1) major adverse cardiac and cerebrovascular events (MACCEs), (2) adverse events within 30 days, (3) hospital length of stay (HLOS), (4) intensive care unit length of stay (ICU LOS), (5) activities of daily living (ADLs), (6) quality of life, (7) cardiac rehabilitation attendance and (8) physical activity behaviour. Methods A systematic search of MEDLINE, Embase, AgeLine and Cochrane library for cohort studies was conducted. Results Eleven studies (n=5733 patients) met the inclusion criteria. Only self-reported physical activity tools were used. Few studies used multivariate analyses to compare active versus inactive patients prior to surgery. When comparing patients who were active versus inactive preoperatively, there were mixed findings for MACCE, 30 day adverse events, HLOS and ICU LOS. Of the studies that adjusted for confounding variables, five studies found a protective, independent association between physical activity and MACCE (n=1), 30-day postoperative events (n=2), HLOS (n=1) and ICU LOS (n=1), but two studies found no protective association for 30-day postoperative events (n=1) and postoperative ADLs (n=1). No studies investigated if activity status before surgery impacted quality of life or cardiac rehabilitation attendance postoperatively. Three studies found that active patients prior to surgery were more likely to be inactive postoperatively. Conclusion Due to the mixed findings, the literature does not presently support that self-reported preoperative physical activity behaviour is associated with postoperative cardiac surgical outcomes. Future studies should objectively measure physical activity, clearly define outcomes and adjust for clinically relevant variables. Registration Trial registration number NCT02219815. PROSPERO number CRD42015023606.

Regulation of Cardiac Sarco(endo)plasmic Reticulum Calcium-ATPases (SERCA2a) in Response to Exercise

Sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) plays an integral role in Ca2+ cycling in the heart. After a myocardial contraction has occurred, SERCA2a is primarily responsible for transporting Ca2+ out of the cytosol into the sarcoplasmic reticulum. Consequently, SERCA2a is key in determining relaxation time and inotropy of subsequent contractions. There are ten different SERCA isoforms in the body, where SERCA2a is the isoform expressed in the heart. Both SERCA2a expression and activity are reduced in models of disease. As such, a large body of research has examined SERCA2a and how it might be used as a means to restore heart function in models of disease. In this chapter, we examine various regulatory mechanisms of SERCA2a and how these mechanisms affect SERCA2a and cardiac function. Transcriptional, protein (e.g., phospholamban and sarcolipin), hormonal (e.g., thyroid hormone and adiponectin), and posttranslational modification (e.g., nitration, glutathionylation, SUMOylation, acetylation, glycosylation, and O-glcNAcylation) processes as they regulate SERCA2a are discussed. Additionally, exercise and its effect on the regulatory mechanisms of SERCA2a is examined.

The association between bouts of moderate to vigorous physical activity and patterns of sedentary behavior with frailty

Objectives To determine if bouts of moderate‐vigorous physical activity (MVPA) and patterns of sedentary behavior are associated with frailty. Method Accelerometry from community‐dwelling adults ≥50 years old (n = 2317) enrolled in the 2003–04 and 2005–06 National Health and Nutrition Examination Survey were used. Bouted (≥10 min) and sporadic (<10 min) durations of MVPA were analyzed based on meeting 0%, 1–49%, 50–99%, and ≥100% of physical activity guidelines (150 min/week of MVPA). Prolonged sedentary behavior were bouts lasting ≥30 min. Breaks from sedentary behavior were defined as any ≥1 min interruption in sedentary behavior. Average intensity (counts/min) and duration (minutes) during breaks were also analyzed. Frailty was measured with a 46‐item frailty index. Results Multivariable linear regression models adjusting for age, sex, education, ethnicity, income, marital status, smoking, alcohol consumption, body mass index, total sedentary time and accelerometer wear time indicated that meeting any percentage of the activity guidelines with bouted and sporadic MVPA was associated with reduced frailty. This relationship peaked at meeting 50–99% of guidelines and was associated with a 1.5 and 2.0 point reduction in the frailty index for bouted and sporadic MVPA, respectively. Two additional prolonged sedentary behavior bouts/day were associated with an additional frailty index deficit while every additional 100 cpm in average break intensity and every 2 min in average break duration were associated with one less deficit. Total sedentary breaks were not associated with frailty. Conclusion These population‐level data give justification for determining if interventions which target short bouts of MVPA and interrupting prolonged, uninterrupted time spent in sedentary behaviors can treat or prevent frailty worsening. HighlightsSporadic and bouts of MVPA were similarly associated with reductions in frailty.Small doses of sporadic or bouted MVPA resulted in significant frailty reductions.Breaking up long bouts of sedentary time was protective of frailty.The intensity and duration during breaks was more important than break frequency.

A systematic review of the association between sedentary behaviors with frailty

Objective: Lifestyle factors such as physical activity are known to reduce the risk of frailty. However, less is known about the frailty‐sedentary behavior relationship. A systematic review was conducted to synthesize the available evidence concerning associations between sedentary behaviors and frailty levels in adults. Method: MEDLINE, Embase, Web of Science, CINAHL, SPORTDiscus, Scopus, and the World Health Organization Clinical Trials Registry were searched up to August 2017 for observational studies in adults >18 years for cohort studies. Included studies identified frailty as a specified outcome using a multi‐component tool. Sedentary behavior was measured by self‐report or objectively. Studies with statistical models adjusting for at least one covariate were included. Meta‐analysis could not be performed due to the heterogeneity in frailty and sedentary behavior measures. Results: Six longitudinal and ten cross‐sectional studies were identified (n = 14, 693 unique participants); sample sizes ranged from 26 to 5871. Studies were generally at a low to moderate risk of bias. Most studies (n = 9) used the Fried criteria to measure frailty. Five studies measured sedentary behavior by questionnaire, with three studies specifically measuring television viewing time. Seven studies measured sedentary time by accelerometry. Thirteen of sixteen studies observed a detrimental association between high amounts of sedentary behaviors and an increased prevalence of frailty or higher frailty levels. Six of seven studies adjusting for physical activity behaviors demonstrated an independent association between sedentary behaviors and frailty. All six longitudinal studies found a negative association between sedentary behaviors and frailty. Conclusions: Sedentary behaviors were associated with a higher prevalence of frailty or higher frailty levels. Longitudinal studies are needed that adjust for physical activity when determining the association between sedentary behaviors and frailty. The efficacy of sedentary behavior reduction outside of physical activity interventions to treat and reverse frailty should also be tested.