The carbon monoxide prodrug oCOm-21 increases Ca2+ sensitivity of the cardiac myofilament.

Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low-dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO-releasing pro-drug, oCOm-21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of -log [Ca2+ ] (pCa) in the range of 9.0-4.5 under five conditions: vehicle, oCOm-21, the oCOm-21 control BP-21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa50 ). oCOm-21, but not BP-21 significantly increased pCa50 compared to vehicle, respectively (pCa50 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm-21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm-21. These results support the hypothesis that oCOm-21-derived CO increases myofilament Ca2+ sensitivity through a heme-dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart.

Association of Preoperative High-Intensity Interval Training With Cardiorespiratory Fitness and Postoperative Outcomes Among Adults Undergoing Major Surgery: A Systematic Review and Meta-Analysis.

Importance: Preoperative high-intensity interval training (HIIT) is associated with improved cardiorespiratory fitness (CRF) and may improve surgical outcomes. Objective: To summarize data from studies comparing the association of preoperative HIIT vs standard hospital care with preoperative CRF and postoperative outcomes. Data Sources: Data sources included Medline, Embase, Cochrane Central Register of Controlled Trials Library, and Scopus databases with no language constraints, including abstracts and articles published before May 2023. Study Selection: The databases were searched for randomized clinical trials and prospective cohort studies with HIIT protocols in adult patients undergoing major surgery. Thirty-four of 589 screened studies met initial selection criteria. Data Extraction and Synthesis: A meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data were extracted by multiple independent observers and pooled in a random-effects model. Main Outcomes and Measures: The primary outcome was change in CRF, as measured by either peak oxygen consumption (V̇o2 peak) or 6-Minute Walk Test (6MWT) distance. Secondary outcomes included postoperative complications; hospital length of stay (LOS); and changes in quality of life, anaerobic threshold, and peak power output. Results: Twelve eligible studies including 832 patients were identified. Pooled results indicated several positive associations for HIIT when compared with standard care either on CRF (V̇o2 peak, 6MWT, anaerobic threshold, or peak power output) or postoperative outcomes (complications, LOS, quality of life), although there was significant heterogeneity in study results. In 8 studies including 627 patients, there was moderate-quality evidence of significant improvement in V̇o2 peak (cumulative mean difference, 2.59 mL/kg/min; 95% CI, 1.52-3.65 mL/kg/min; P < .001). In 8 studies including 770 patients, there was moderate-quality evidence of a significant reduction in complications (odds ratio, 0.44; 95% CI, 0.32-0.60; P < .001). There was no evidence that HIIT differed from standard care in hospital LOS (cumulative mean difference, -3.06 days; 95% CI, -6.41 to 0.29 days; P = .07). The analysis showed a high degree of heterogeneity in study outcomes and an overall low risk of bias. Conclusions and Relevance: The results of this meta-analysis suggest that preoperative HIIT may be beneficial for surgical populations through the improvement of exercise capacity and reduced postoperative complications. These findings support including HIIT in prehabilitation programs before major surgery. The high degree of heterogeneity in both exercise protocols and study results supports the need for further prospective, well-designed studies.

Sarco/endoplasmic reticulum calcium ATPase activity is unchanged despite increased myofilament calcium sensitivity in Zucker type 2 diabetic fatty rat heart.

Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calcium (Ca2+) regulation. However, there is emerging evidence that Ca2+ mishandling alone is insufficient to fully explain diabetic heart dysfunction, with focus shifting to the properties of the myofilament proteins. Our aim was to examine the effects of diabetes on myofilament Ca2+ sensitivity and Ca2+ handling in left ventricular tissues isolated from the same type 2 diabetic rat hearts. We measured the force-pCa relationship in skinned left ventricular cardiomyocytes isolated from 20-week-old type 2 diabetic and non-diabetic rats. Myofilament Ca2+ sensitivity was greater in the diabetic relative to non-diabetic cardiomyocytes, and this corresponded with lower phosphorylation of cardiac troponin I (cTnI) at ser23/24 in the diabetic left ventricular tissues. Protein expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), phosphorylation of phospholamban (PLB) at Ser16, and SERCA/PLB ratio were lower in the diabetic left ventricular tissues. However, the maximum SERCA Ca2+ uptake rate was not different between the diabetic and non-diabetic myocardium. Our data suggest that impaired contractility in the diabetic heart is not caused by SERCA Ca2+ mishandling. This study highlights the important role of the cardiac myofilament and provides new insight on the pathophysiology of diabetic heart dysfunction.

Treadmill running increases the calcium sensitivity of myofilaments in diabetic rats.

The cardiovascular benefits of regular exercise are unequivocal, yet patients with type 2 diabetes respond poorly to exercise due to a reduced cardiac reserve. The contractile response of diabetic cardiomyocytes to ß-adrenergic stimulation is attenuated, which may result in altered myofilament calcium sensitivity and posttranslational modifications of cardiac troponin I (cTnI). Treadmill running increases myofilament calcium sensitivity in nondiabetic rats, and thus we hypothesized that endurance training would increase calcium sensitivity of diabetic cardiomyocytes and alter site-specific phosphorylation of cTnI. Calcium sensitivity, or pCa50, was measured in Zucker diabetic fatty (ZDF), nondiabetic (nDM), and diabetic (DM) rat hearts after 8 wk of either a sedentary (SED) or progressive treadmill running (TR) intervention. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+]). Specific phospho-sites on cTnI and O-GlcNAcylation were quantified by immunoblot and total protein phosphorylation by fluorescent gel staining (ProQ Diamond). The novel finding in this study was that training increased pCa50 in both DM and nDM cardiomyocytes (P = 0.009). Phosphorylation of cTnI amino acid residues Ser23/24, a crucial protein kinase A site, and Threonine (Thr)144 was lower in DM hearts, but there was no effect of training on site-specific phosphorylation. In addition, total phosphorylation and O-GlcNAcylation levels were not different between SED and TR groups. These findings suggest that regular exercise may benefit the diabetic heart by specifically targeting myofilament contractile function.NEW & NOTEWORTHY We examined the effects of training on the myofilament calcium in diabetic rat hearts. After 8 wk of treadmill running, both nondiabetic and diabetic cardiomyocytes had increased myofilament calcium sensitivity compared with their sedentary counterparts, but there was no effect of training on the phosphorylation or O-GlcNAcylation status of myofilament proteins measured in this study. These data highlight one potential mechanism capable of reversing, in part, reduced cardiac reserve in the diabetic heart.

Short-term high-intensity interval training improves fitness before surgery: A randomized clinical trial.

PURPOSE: Improving cardiopulmonary reserve, or peak oxygen consumption( V ˙ O2peak ), may reduce postoperative complications; however, this may be difficult to achieve between diagnosis and surgery. Our primary aim was to assess the efficacy of an approximate 14-session, preoperative high-intensity interval training(HIIT) program to increase V ˙ O2peak by a clinically relevant 2 ml·kg-1 ·min-1 . Our secondary aim was to document clinical outcomes. METHODOLOGY: In this prospective study, participants aged 45-85 undergoing major abdominal surgery were randomized to standard care or 14 sessions of HIIT over 4 weeks. HIIT sessions involved approximately 30 min of stationary cycling. Interval training alternated 1 min of high (with the goal of reaching 90% max heart rate at least once during the session) and low/moderate-intensity cycling. Cardiopulmonary exercise testing(CPET) measured the change in V ˙ O2peak from baseline to surgery. Clinical outcomes included postoperative complications, length of stay(LOS), and Short Form 36 quality of life questionnaire(SF-36). RESULTS: Of 63 participants, 46 completed both CPETs and 50 completed clinical follow-up. There was a significant improvement in the HIIT group's mean ± SD V ˙ O2peak (HIIT 2.87 ± 1.94 ml·kg1 ·min-1 vs standard care 0.15 ± 1.93, with an overall difference of 2.73 ml·kg1 ·min-1 95%CI [1.53, 3.93] p < 0.001). There were no statistically significant differences between groups for clinical outcomes, although the observed differences consistently favored the exercise group. This was most notable for total number of complications (0.64 v 1.16 per patient, p = 0.07), SF-36 physical component score (p = 0.06), and LOS (mean 5.5 v 7.4 days, p = 0.07). CONCLUSIONS: There was a significant improvement in V ˙ O2peak with a four-week preoperative HIIT program. Further appropriately powered work is required to explore the impact of preoperative HIIT on postoperative clinical outcomes.

The associations between maternal BMI and gestational weight gain and health outcomes in offspring at age 1 and 7 years.

In secondary analyses of a randomised controlled trial of exercise during pregnancy, we examined associations between mid-pregnancy maternal body mass index (BMI) and excessive gestational weight gain (GWG) with offspring health. Follow-up data were available on 57 mother-child pairs at 1-year and 52 pairs at 7-year follow-ups. Clinical assessments included body composition and fasting blood tests. At age 1 year, increased maternal BMI in mid-gestation was associated with greater weight standard deviation scores (SDS) in the offspring (p = 0.035), with no observed associations for excessive GWG. At age 7 years, greater maternal BMI was associated with increased weight SDS (p < 0.001), BMI SDS (p = 0.005), and total body fat percentage (p = 0.037) in their children. Irrespective of maternal BMI, children born to mothers with excessive GWG had greater abdominal adiposity (p = 0.043) and less favourable lipid profile (lower HDL-C and higher triglycerides). At 7 years, maternal BMI and excessive GWG had compounded adverse associations with offspring adiposity. Compared to offspring of mothers with overweight/obesity plus excessive GWG, children of normal-weight mothers with adequate and excessive GWG were 0.97 and 0.64 SDS lighter (p = 0.002 and p = 0.014, respectively), and 0.98 and 0.63 SDS leaner (p = 0.001 and p = 0.014, respectively). Both greater maternal BMI in mid-pregnancy and excessive GWG were independently associated with increased adiposity in offspring at 7 years.

Increased myofilament calcium sensitivity is associated with decreased cardiac troponin I phosphorylation in the diabetic rat heart.

NEW FINDINGS: What is the central question of this study? In Zucker Diabetic Fatty rats, does cardiomyocyte myofilament function change through the time course of diabetes and what are the mechanisms behind alterations in calcium sensitivity? What is the main finding and its importance? Zucker Diabetic Fatty rats had increased myofilament calcium sensitivity and reduced phosphorylation at cardiac troponin I without differential O-GlcNAcylation. ABSTRACT: The diabetic heart has impaired systolic and diastolic function independent of other comorbidities. The availability of calcium is altered, but does not fully explain the cardiac dysfunction seen in the diabetic heart. Thus, we explored if myofilament calcium regulation of contraction is altered while also categorizing the levels of phosphorylation and O-GlcNAcylation in the myofilaments. Calcium sensitivity (pCa50 ) was measured in Zucker Diabetic Fatty (ZDF) rat hearts at the initial stage of diabetes (12 weeks old) and after 8 weeks of uncontrolled hyperglycaemia (20 weeks old) and in non-diabetic (nDM) littermates. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+ ]). Fluorescent gel stain (ProQ Diamond) was used to measure total protein phosphorylation. Specific phospho-sites on cardiac troponin I (cTnI) and total cTnI O-GlcNAcylation were quantified using immunoblot. pCa50 was greater in both 12- and 20-week-old diabetic (DM) rats compared to nDM littermates (P = 0.0001). Total cTnI and cTnI serine 23/24 phosphorylation were lower in DM rats (P = 0.003 and P = 0.01, respectively), but cTnI O-GlcNAc protein expression was not different. pCa50 is greater in DM rats and corresponds with an overall reduction in cTnI phosphorylation. These findings indicate that myofilament calcium sensitivity is increased and cTnI phosphorylation is reduced in ZDF DM rats and suggests an important role for cTnI phosphorylation in the DM heart.

Protein O-GlcNAcylation in the heart.

O-GlcNAcylation is a ubiquitous post-translational modification that is extremely labile and plays a significant role in physiology, including the heart. Sustained activation of cardiac O-GlcNAcylation is frequently associated with alterations in cellular metabolism, leading to detrimental effects on cardiovascular function. This is particularly true during conditions such as diabetes, hypertension, cardiac remodelling, heart failure and arrhythmogenesis. Paradoxically, transient elevation of cardiac protein O-GlcNAcylation can also exert beneficial effects in the heart. There is compelling evidence to suggest that a complex interaction between O-GlcNAcylation and phosphorylation also exists in the heart. Beyond direct functional consequences on cardiomyocytes, O-GlcNAcylation also acts indirectly by altering the function of transcription factors that affect downstream signalling. This review focuses on the potential cardioprotective role of protein O-GlcNAcylation during ischaemia-reperfusion injury, the deleterious consequences of chronically elevated O-GlcNAc levels, the interplay between O-GlcNAcylation and phosphorylation in the cardiomyocytes and the effects of O-GlcNAcylation on other major non-myocyte cell types in the heart.

Additional cardiovascular fitness when progressing from moderate- to high-intensity exercise training in previously trained breast cancer survivors.

PURPOSE: Cardiovascular disease, often secondary to chemotherapy, is the leading cause of death in BC survivors. Increased aerobic capacity improves post-rehabilitation survival; however, many cancer rehabilitation programs are limited to lower intensity training. High-intensity interval training (HIIT) is associated with the largest improvements in aerobic capacity; therefore, this study aimed to determine whether HIIT would cause a greater increase in VO2peak than continuous moderate-intensity (MICT) exercise in previously trained BC survivors. METHODS: Twenty BC survivors who had completed a low/moderate-intensity exercise rehabilitation program performed a VO2peak test and received a dual-energy X-ray absorptiometry (DXA) scan at baseline and after randomization into a 12-week HIIT or MICT program. ANOVA with repeated measures determined the effects of the different training programs on aerobic capacity and body composition. RESULTS: Both groups began the training program near or above age- and sex-matched VO2peak norms. Pre- to post-intervention improvements in VO2peak (P = 0.006) and waist circumference (P = 0.007) were found in both groups; however, there were no between-group differences. Minute ventilation and peak workload increased in the HIIT group (P < 0.05) but not the MICT group. Body composition was not different after either training program. CONCLUSIONS: These data suggest that transitioning from low/moderate-intensity exercise to moderate/high-intensity exercise causes further clinically relevant increases in VO2peak in previously trained BC survivors. HIIT did not cause a significantly greater improvement in VO2peak than MICT; however, future studies with greater intensity and frequency of training are encouraged.

HIIT Improves Left Ventricular Exercise Response in Adults with Type 2 Diabetes.

Type 2 diabetes is associated with reduced left ventricular reserve. It is unclear whether exercise training improves left ventricular function in people with type 2 diabetes. PURPOSE: This study aimed to determine whether 3 months of high-intensity interval training (HIIT) improves left ventricular function during exercise in adults with type 2 diabetes. METHODS: Participants performed a V˙O2peak test and received a DXA scan and total blood volume measurement at baseline. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular stroke volume (LVSV) were then measured at rest and during low- and moderate-intensity semirecumbent exercise in adults with type 2 diabetes before and after 3 months of HIIT (n = 11) or no training (control) (n = 5). The effects of HIIT were determined using repeated-measures ANOVA. RESULTS: HIIT increased V˙O2peak by approximately 15% (P < 0.002) but did not change body composition or total blood volume. LVESV decreased and LVEDV and LVSV increased from rest to moderate-intensity exercise in both groups at baseline (all P < 0.01). Three months of HIIT increased LVEDV (P = 0.008) and LVSV (P = 0.02) at all conditions, but there was no difference in controls (all P > 0.05). HIIT augmented the reduction in LVESV from rest to moderate-intensity exercise (P < 0.04), but LVESV was unchanged in controls. Increased LVEDV explained 51% of the change in LVSV after HIIT intervention. Mitral inflow parameters and mitral annular velocities were unaffected by HIIT (all P > 0.05). CONCLUSIONS: HIIT training increased the LVSV response to exercise in adults with type 2 diabetes. These data suggest that HIIT can improve LV filling and emptying during exercise and reverse early cardiac consequences of type 2 diabetes.

Exercise in pregnancy: 1-year and 7-year follow-ups of mothers and offspring after a randomized controlled trial.

There are limited data on long-term outcomes of mothers or their offspring following exercise interventions during pregnancy. We assessed long-term effects of an exercise intervention (home-based stationary cycling) between 20-36 weeks of gestation on anthropometry and body composition in mothers and offspring after 1 and 7 years. 84 women were randomised to intervention or usual activity, with follow-up data available for 61 mother-child pairs (38 exercisers) at 1 year and 57 (33 exercisers) at 7 years. At 1 year, there were no observed differences in measured outcomes between mothers and offspring in the two groups. At the 7-year follow-up, mothers were mostly similar, except that exercisers had lower systolic blood pressure (-6.2 mmHg; p = 0.049). However, offspring of mothers who exercised during pregnancy had increased total body fat (+3.2%; p = 0.034) and greater abdominal (+4.1% android fat; p = 0.040) and gynoid (+3.5% gynoid fat; p = 0.042) adiposity compared with controls. Exercise interventions beginning during pregnancy may be beneficial to long-term maternal health. However, the initiation of exercise during pregnancy amongst sedentary mothers may be associated with adverse effects in the offspring during childhood. Larger follow-up studies are required to investigate long-term effects of exercise in pregnancy.

Protocol, and practical challenges, for a randomised controlled trial comparing the impact of high intensity interval training against standard care before major abdominal surgery: study protocol for a randomised controlled trial.

BACKGROUND: Risk factors, such as the number of pre-existing co-morbidities, the extent of the underlying pathology and the magnitude of the required operation, cannot be changed before surgery. It may, however, be possible to improve the cardiopulmonary fitness of the patient with an individualised exercise program. We are performing a randomised controlled trial (RCT) assessing the impact of High Intensity Interval Training (HIIT) on preoperative cardiopulmonary fitness and postoperative outcomes in patients undergoing major abdominal surgery. METHODS: Consecutive eligible patients undergoing elective abdominal surgery are being randomised to HIIT or standard care in a 1:1 ratio. Participants allocated to HIIT will perform 14 exercise sessions on a stationary cycle ergometer, over a period of 4-6 weeks before surgery. The sessions, which are individualised, aim to start with ten repeated 1-min blocks of intense exercise with a target of reaching a heart rate exceeding 90% of the age predicted maximum, followed by 1 min of lower intensity cycling. As endurance improves, the duration of exercise is increased to achieve five 2-min intervals of high intensity exercise followed by 2 min of lower intensity cycling. Each training session lasts approximately 30 min. The primary endpoint, change in peak oxygen consumption (Peak VO2) measured during cardiopulmonary exercise testing, is assessed at baseline and before surgery. Secondary endpoints include postoperative complications, length of hospital stay and three clinically validated scores: the surgical recovery scale; the postoperative morbidity survey; and the SF-36 quality of life score. The standard deviation for changes in Peak VO2 will be assessed after the first 30 patients and will be used to calculate the required sample size. DISCUSSION: We want to assess if 14 sessions of HIIT is sufficient to improve Peak VO2 by 2 mL/kg/min in patients undergoing major abdominal surgery and to explore the best clinical endpoint for a subsequent RCT designed to assess if improving Peak VO2 will translate into improving clinical outcomes after surgery. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12617000587303 . Registered on 26 April 2017.

Impaired ventricular filling limits cardiac reserve during submaximal exercise in people with type 2 diabetes.

BACKGROUND: Attenuated increases in ventricular stroke volume during exercise are common in type 2 diabetes and contribute to reduced aerobic capacity. The purpose of this study was to determine whether impaired ventricular filling or reduced systolic ejection were responsible for the attenuated stroke volume reserve in people with uncomplicated type 2 diabetes. METHODS: Peak aerobic capacity and total blood volume were measured in 17 people with diabetes and 16 non-diabetic controls with no evidence of cardiovascular disease. Left ventricular volumes and other systolic and diastolic functional parameters were measured with echocardiography at rest and during semi-recumbent cycle ergometry at 40 and 60% of maximal aerobic power and compared between groups. RESULTS: People with diabetes had reduced peak aerobic capacity and heart rate reserve, and worked at lower workloads than non-diabetic controls. Cardiac output, stroke volume and ejection fraction were not different at rest, but increased less in people with diabetes during exercise. Left ventricular end systolic volume was not different between groups in any condition but end diastolic volume, although not different at rest, was smaller in people with diabetes during exercise. Total blood volume was not different between the groups, and was only moderately associated with left ventricular volumes. CONCLUSIONS: People with type 2 diabetes exhibit an attenuated increase in stroke volume during exercise attributed to an inability to maintain/increase left ventricular filling volumes at higher heart rates. This study is the first to determine the role of filling in the blunted cardiac reserve in adults with type 2 diabetes.

Exercise Training Improves but Does Not Normalize Left Ventricular Systolic and Diastolic Function in Adolescents With Type 1 Diabetes.

OBJECTIVE: To determine the impact of 20 weeks of exercise training in aerobic capacity on left ventricular function and glycemic control in adolescents with and without type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifty-three adolescents with type 1 diabetes (aged 15.6 years) were divided into two groups: exercise training (n = 38) and nontraining (n = 15). Twenty-two healthy adolescents without diabetes (aged 16.7 years) were included and, with the 38 participants with type 1 diabetes, participated in a 20-week exercise-training intervention. Assessments included VO2max and body composition. Left ventricular parameters were obtained at rest and during acute exercise using MRI. RESULTS: Exercise training improved aerobic capacity (10%) and stroke volume (6%) in both trained groups, but the increase in the group with type 1 diabetes remained lower than trained control subjects. Increased stroke volume in adolescents with type 1 diabetes resulted from greater left ventricular contractility (9% increase in ejection fraction and an 11% reduction in end-systolic volumes) and, to a lesser extent, improved left ventricular filling (6%), suggesting that impaired diastolic function can be affected by exercise training in adolescents with type 1 diabetes. Insulin use decreased by ∼10%, but no change in glycemic status was observed. CONCLUSIONS: These data demonstrate that in adolescents, the impairment in left ventricular function seen with type 1 diabetes can be improved, although not normalized, with regular intense physical activity. Importantly, diastolic dysfunction, a common mechanism causing heart failure in older subjects with diabetes, appears to be partially reversible in this age group.

Resting heart rate variability and exercise capacity in Type 1 diabetes.

People with type 1 diabetes (T1D) have lower exercise capacity (V̇O2max) than their age-matched nondiabetic counterparts (CON), which might be related to cardiac autonomic dysfunction. We examined whether Heart Rate Variability (HRV; indicator of cardiac autonomic modulation) was associated with exercise capacity in those with and without T1D. Twenty-three participants with uncomplicated T1D and 17 matched CON were recruited. Heart rate (HR; ECG), blood pressure (BP; finger photo-plethysmography), and respiratory rate (respiratory belt) were measured during baseline, paced-breathing and clinical autonomic reflex tests (CARTs); deep breathing, lying-to-stand, and Valsalva maneuver. Baseline and paced-breathing ECG were analyzed for HRV (frequency-domain). Exercise capacity was determined during an incremental cycle ergometer test while V̇O2, 12-lead ECG, and BP were measured. In uncomplicated T1D, resting HR was elevated and resting HRV metrics were reduced, indicative of altered cardiac parasympathetic modulation; this was generally undetected by the CARTs. However, BP and plasma catecholamines were not different between groups. In T1D, V̇O2max tended to be lower (P = 0.07) and HR reserve was lower (P < 0.01). Resting Total Power (TP) had stronger positive associations with V̇O2max (R2 ≥ 0.3) than all other traditional indicators such as age, resting HR, and self-reported exercise (R2 = 0.042-0.3) in both T1D and CON Alterations in cardiac autonomic modulation are an early manifestation of uncomplicated T1D. Total Power was associated with reduced exercise capacity regardless of group, and these associations were generally stronger than traditional indicators.

ß-Adrenergic Responsiveness in the Type 2 Diabetic Heart: Effects on Cardiac Reserve.

Type 2 diabetes (T2D) is associated with reduced cardiac reserve and aerobic capacity. Altered myocardial autonomic nervous regulation has been demonstrated in humans with diabetes (indirectly) and animal models (directly). PURPOSE: This study aimed to determine the chronotopic and inotropic response of the type 2 diabetic heart to ß-adrenergic stimulation. METHODS: Eight people with uncomplicated T2D and seven matched controls performed a dual-energy x-ray absorptiometry scan and V˙O2peak test. Plasma catecholamines were determined at rest and during peak exercise. On a second visit, HR and left ventricular contractility were assessed using echocardiography during supine rest, parasympathetic blockade (atropine), and during incremental ß-adrenergic stimulation (dobutamine). RESULTS: V˙O2peak and HR reserve were lower in T2D (P < 0.05) as expected. Both groups increased norepinephrine comparably (P = 0.23) during peak exercise; however, epinephrine increased less in the T2D group (P < 0.05). The dobutamine dose required to achieve 85% of age-predicted maximal HR was 36% higher in CON (P < 0.05). Resting HR was higher (P < 0.01) and stroke volume indexed to fat free mass was smaller (P < 0.05) in T2D. During dobutamine infusion the response (% change) in HR, end-diastolic volumeFFM, stroke volume, ejection fraction, and cardiac output were not different between the groups. However, HR was higher (P < 0.01) and end-diastolic volume indexed to fat free mass (P < 0.01), stroke volumeFFM (P < 0.01), ejection fraction (P < 0.05), and stroke work (P < 0.01) were lower in T2D. CONCLUSIONS: Although the type 2 diabetic heart worked at smaller volumes, the HR and contractile response to ß-adrenergic stimulation were unaffected by diabetes. The reduced cardiac reserve observed in uncomplicated T2D was not explained by impaired myocardial sympathetic responsiveness but may reflect changes in the loading conditions or function of the diabetic left ventricle.

'Exercise snacks' before meals: a novel strategy to improve glycaemic control in individuals with insulin resistance.

AIMS/HYPOTHESIS: The aim of this study was to investigate whether small doses of intense exercise before each main meal ('exercise snacks') would result in better blood glucose control than a single bout of prolonged, continuous, moderate-intensity exercise in individuals with insulin resistance. METHODS: Nine individuals completed three exercise interventions in randomised order. Measures were recorded across 3 days with exercise performed on the middle day, as either: (1) traditional continuous exercise (CONT), comprising 30 min moderate-intensity (60% of maximal heart rate [HRmax]) incline walking before dinner; (2) exercise snacking (ES), consisting of 6 × 1 min intense (90% HRmax) incline walking intervals 30 min before each meal; or (3) composite exercise snacking (CES), encompassing 6 × 1 min intervals alternating between walking and resistance-based exercise, 30 min before meals. Meal timing and composition were controlled within participants for exercise interventions. RESULTS: ES attenuated mean 3 h postprandial glucose concentration following breakfast (by 1.4 ± 1.5 mmol/l, p = 0.02) but not lunch (0.4 ± 1.0 mmol/l, p = 0.22), and was more effective than CONT following dinner (0.7 ± 1.5 mmol/l below CONT; p = 0.04). ES also reduced 24 h mean glucose concentration by 0.7 ± 0.6 mmol/l (p = 0.01) and this reduction persisted for the subsequent 24 h (lower by 0.6 ± 0.4 mmol/l vs CONT, relative to their baselines; p = 0.01). CES was just as effective as ES (p > 0.05 for all glycaemic variables) at improving glycaemic control. CONCLUSIONS/INTERPRETATION: Dosing exercise as brief, intense 'exercise snacks' before main meals is a time-efficient and effective approach to improve glycaemic control in individuals with insulin resistance.

Endovascular renal denervation: a novel sympatholytic with relevance to chronic kidney disease.

Endovascular renal denervation (sympathectomy) is a novel procedure developed for the treatment of resistant hypertension. Evidence suggests that it reduces both afferent and efferent sympathetic nerve activity, which may offer clinical benefit over and above any blood pressure-lowering effect. Studies have shown objective improvements in left ventricular mass, ventricular function, central arterial stiffness, central haemodynamics, baroreflex sensitivity and arrhythmia frequency. Benefits have also been seen in insulin resistance, microalbuminuria and glomerular filtration rate. In chronic kidney disease, elevated sympathetic activity has been causally linked to disease progression and cardiovascular sequelae. Effecting a marked reduction in sympathetic hyperactivity may herald a significant step in the management of this and other conditions. In this in-depth review, the pathophysiology and clinical significance of the sympatholytic effects of endovascular renal denervation are discussed.