Circuit resistance training and cardiovascular health in breast cancer survivors.

OBJECTIVE: Cardiovascular disease is the leading cause of death in breast cancer survivors. While evidence shows circuit resistance training (CRT) is effective for improving muscle and cardiorespiratory fitness, whether CRT is an efficacious therapy for decreasing cardiovascular risk in cancer survivors is unclear. METHODS: Fifty-one breast cancer survivors were recruited to either 12 weeks CRT (n = 26), or a non-exercising wait-list control (n = 25). Two supervised 60 min CRT sessions per week were undertaken, comprising resistance and functional exercises, and aerobic exercise stations. Primary outcome measure was the gold-standard assessment of arterial stiffness, aortic pulse wave velocity (PWV). Secondary outcomes included: cardiorespiratory fitness (CRF), upper and lower body strength, arterial wave reflections, central blood pressure and rate pressure product. RESULTS: Compared to the control group, the CRT group had a statistically significant medium effect decrease in PWV 0.9 m/s (95% CI: 0.1, 1.7). There were large effect improvements in VO2 max (4.3 ml kg-1  min-1 , 95% CI: 5.8, 2.8), upper and lower body strength (3.7 kg, 95% CI: 1.9, 5.6 and 10.4 kg, 1.6, 19.1) respectively. CONCLUSION: Findings support the existing literature demonstrating that 12 weeks CRT improves muscle and cardiorespiratory fitness and is also an effective strategy for decreasing a proven cardiovascular risk factor in breast cancer survivors.

Cardiorespiratory fitness predicts cardiovascular health in breast cancer survivors, independent of body composition, age and time post-treatment completion.

BACKGROUND: Breast cancer treatment may increase non-cancer related mortality risk due to unintended cardiovascular consequences. The aim of this study was to investigate the strongest correlate of cardiovascular health (CVH) in female breast cancer survivors, cardiorespiratory fitness or fatness. METHODS: Fifty-one women (59 ± 9 years, BMI 26.4 ± 4.8 kg/m2) previously diagnosed and treated for primary breast cancer were assessed using pulse wave analysis to determine central arterial wave reflection (augmentation index, AIx) and central systolic blood pressure (cSBP). A composite Z score calculated which incorporated central double product and AIx, as an indicator of CVH. Dual energy X-ray absorptiometry was used to obtain total body fat percentage (BF%). Cardiorespiratory fitness was determined using the single-stage walk test to predict maximal oxygen uptake ([Formula: see text]). RESULTS: Linear regression analysis revealed that fitness was associated with AIx after adjusting for BF %, age and time post-treatment completion (ß = - 0.271, p = 0.010). A significant association between BF% and AIx after adjusting for fitness and age was found (ß = 0.166, p = 0.0005); however, this association was lost when time post-treatment was included in the model (ß = 0.166, p = 0.167). Both fitness (ß = - 0.347, p = 0.0005) and BF% (ß = 0.333, p = 0.013) were independently associated with CVH in the fully adjusted model. CONCLUSIONS: This study provides evidence for an association between cardiorespiratory fitness and cardiovascular health in female breast cancer survivors. While fatness may be associated with cardiovascular health, it appears to be more strongly associated with age.

Inhibition of calcium/calmodulin-dependent kinase II restores contraction and relaxation in isolated cardiac muscle from type 2 diabetic rats.

BACKGROUND: Calcium/calmodulin-dependent kinase II-delta (CaMKIIδ) activity is enhanced during hyperglycemia and has been shown to alter intracellular calcium handling in cardiomyocytes, ultimately leading to reduced cardiac performance. However, the effects of CaMKIIδ on cardiac contractility during type 2 diabetes are undefined. METHODS: We examined the expression and activation of CaMKIIδ in right atrial appendages from non-diabetic and type 2 diabetic patients (n = 7 patients per group) with preserved ejection fraction, and also in right ventricular tissue from Zucker Diabetic Fatty rats (ZDF) (n = 5-10 animals per group) during early diabetic cardiac dysfunction, using immunoblot. We also measured whole heart function of ZDF and control rats using echocardiography. Then we measured contraction and relaxation parameters of isolated trabeculae from ZDF to control rats in the presence and absence of CaMKII inhibitors. RESULTS: CaMKIIδ phosphorylation (at Thr287) was increased in both the diabetic human and animal tissue, indicating increased CaMKIIδ activation in the type 2 diabetic heart. Basal cardiac contractility and relaxation were impaired in the cardiac muscles from the diabetic rats, and CaMKII inhibition with KN93 partially restored contractility and relaxation. Autocamtide-2-related-inhibitor peptide (AIP), another CaMKII inhibitor that acts via a different mechanism than KN93, fully restored cardiac contractility and relaxation. CONCLUSIONS: Our results indicate that CaMKIIδ plays a key role in modulating performance of the diabetic heart, and moreover, suggest a potential therapeutic role for CaMKII inhibitors in improving myocardial function during type 2 diabetes.

The Type 2 Diabetic Heart: Its Role in Exercise Intolerance and the Challenge to Find Effective Exercise Interventions.

The metabolic and microvascular benefits of regular exercise for people with diabetes are unequivocal. However, cardiovascular disease, which disproportionately affects people with diabetes, is not reduced by regular exercise, and heart disease remains the leading cause of death for people with type 2 diabetes. 'Subclinical' changes in the function of the diabetic left ventricle are common and reduce cardiac reserve and exercise capacity. This review describes the changes in resting and exercising left ventricular function, and the possible causes of these changes, and introduces the possibility that more vigorous exercise may be needed to improve left ventricular function and reduce rates of cardiovascular disease in people with type 2 diabetes.

Cardiovascular control during exercise in type 2 diabetes mellitus.

Controlled studies of male and female subjects with type 2 diabetes mellitus (DM) of short duration (~3-5 years) show that DM reduces peak VO2 (L·min(-1) and mL·kg(-1)·min(-1)) by an average of 12-15% and induces a greater slowing of the dynamic response of pulmonary VO2 during submaximal exercise. These effects occur in individuals less than 60 years of age but are reduced or absent in older males and are consistently associated with significant increases in the exercise pressor response despite normal resting blood pressure. This exaggerated pressor response, evidence of exertional hypertension in DM, is manifest during moderate submaximal exercise and coincides with a more constrained vasodilation in contracting muscles. Maximum vasodilation during contractions involving single muscle groups is reduced by DM, and the dynamic response of vasodilation during submaximal contractions is slowed. Such vascular constraint most likely contributes to exertional hypertension, impairs dynamic and peak VO2 responses, and reduces exercise tolerance. There is a need to establish the effect of DM on dynamic aspects of vascular control in skeletal muscle during whole-body exercise and to clarify contributions of altered cardiovascular control and increased arterial stiffness to exertional hypertension.

Increased Efferent Cardiac Sympathetic Nerve Activity and Defective Intrinsic Heart Rate Regulation in Type 2 Diabetes.

Elevated sympathetic nerve activity (SNA) coupled with dysregulated ß-adrenoceptor (ß-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the ß-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to ß-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular ß1-AR and Gs (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial ß2-AR and Gi (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac ß-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart.

Impaired relaxation despite upregulated calcium-handling protein atrial myocardium from type 2 diabetic patients with preserved ejection fraction.

BACKGROUND: Diastolic dysfunction is a key factor in the development and pathology of cardiac dysfunction in diabetes, however the exact underlying mechanism remains unknown, especially in humans. We aimed to measure contraction, relaxation, expression of calcium-handling proteins and fibrosis in myocardium of diabetic patients with preserved systolic function. METHODS: Right atrial appendages from patients with type 2 diabetes mellitus (DM, n = 20) and non-diabetic patients (non-DM, n = 36), all with preserved ejection fraction and undergoing coronary artery bypass grafting (CABG), were collected. From appendages, small cardiac muscles, trabeculae, were isolated to measure basal and ß-adrenergic stimulated myocardial function. Expression levels of calcium-handling proteins, sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and phospholamban (PLB), and of ß1-adrenoreceptors were determined in tissue samples by Western blot. Collagen deposition was determined by picro-sirius red staining. RESULTS: In trabeculae from diabetic samples, contractile function was preserved, but relaxation was prolonged (Tau: 74 ± 13 ms vs. 93 ± 16 ms, non-DM vs. DM, p = 0.03). The expression of SERCA2a was increased in diabetic myocardial tissue (0.75 ± 0.09 vs. 1.23 ± 0.15, non-DM vs. DM, p = 0.007), whereas its endogenous inhibitor PLB was reduced (2.21 ± 0.45 vs. 0.42 ± 0.11, non-DM vs. DM, p = 0.01). Collagen deposition was increased in diabetic samples. Moreover, trabeculae from diabetic patients were unresponsive to ß-adrenergic stimulation, despite no change in ß1-adrenoreceptor expression levels. CONCLUSIONS: Human type 2 diabetic atrial myocardium showed increased fibrosis without systolic dysfunction but with impaired relaxation, especially during ß-adrenergic challenge. Interestingly, changes in calcium-handling protein expression suggests accelerated active calcium re-uptake, thus improved relaxation, indicating a compensatory calcium-handling mechanism in diabetes in an attempt to maintain diastolic function at rest despite impaired relaxation in the diabetic fibrotic atrial myocardium. Our study addresses important aspects of the underlying mechanisms of diabetes-associated diastolic dysfunction, which is crucial to developing new therapeutic treatments.

Systolic and diastolic abnormalities reduce the cardiac response to exercise in adolescents with type 2 diabetes.

OBJECTIVE: To better understand the cardiac limitations during exercise in adolescents with type 2 diabetes mellitus (T2DM), we measured left ventricular performance with magnetic resonance imaging (MRI) during exercise in diabetic and nondiabetic adolescents. RESEARCH DESIGN AND METHODS: Thirteen subjects with T2DM, 27 overweight/obese nondiabetic (ObeseND) subjects, and 19 nondiabetic nonobese control subjects were recruited. Cardiac (left ventricular) MRI scans were performed at rest and during submaximal exercise. RESULTS: Vo2 peak indexed to fat-free mass was reduced in T2DM and ObeseND subjects compared with control subjects (P < 0.0001). Indexed cardiac output increased less during exercise and was 20% lower in T2DM subjects due to reduced stroke volume. This was a consequence of reduced ventricular filling with smaller end-diastolic volume, which decreased further during exercise in T2DM subjects, but not in ObeseND or control subjects. End-systolic volume was also smaller in T2DM subjects. These changes were associated with increased resting and exercise diastolic blood pressure, and total peripheral resistance in T2DM subjects. CONCLUSIONS: Independently of obesity, T2DM impairs cardiac function during exercise in adolescents.

Structural and functional cardiac abnormalities in adolescent girls with poorly controlled type 2 diabetes.

OBJECTIVE: Type 2 diabetes is associated with left ventricular hypertrophy (LVH) and diastolic dysfunction, which may eventually lead to clinical heart failure. We sought to determine the cardiovascular effects of adolescent-onset type 2 diabetes. RESEARCH DESIGN AND METHODS: We recruited diabetic girls (8 with type 2 and 11 with type 1 diabetes) from a hospital diabetes service and nondiabetic control subjects (9 lean and 11 overweight) from the schools of the diabetic subjects. Echocardiography and measurements were performed by a single observer, blinded to subject group allocation, and included M-mode left ventricular dimensions, two-dimensional left ventricular mass, Doppler diastolic flows, estimation of left ventricular filling pressure, and systolic longitudinal motion. Left ventricular mass was indexed to height and fat-free body mass. ANOVA was used to compare the groups. RESULTS: The groups were similar in age and height, but significant differences in body composition were observed. Subjects with type 2 diabetes had larger left ventricular dimensions and left ventricular mass, which persisted when indexed to height. Diastolic filling was impaired in both diabetic groups, and systolic longitudinal function was lower in the type 2 diabetic group. Half of the group with type 2 diabetes met the published criteria for LVH and left ventricular dilatation; 25% had evidence of elevated left ventricular filling pressure in association with structural abnormalities. CONCLUSIONS: This study has demonstrated preclinical abnormalities of cardiac structure and function in adolescent girls with type 2 diabetes, despite the short duration of diabetes and highlights the potential high cardiovascular risk occurring in adolescent type 2 diabetes.

Variation in blood levels of inflammatory markers related and unrelated to smoking cessation in women.

This study assessed the influence of short-term changes in smoking habit on blood levels of inflammatory markers, which have been associated with increased cardiovascular risk. Five inflammatory markers were measured before and 6 weeks after attempting smoking cessation in 138 healthy women. In the 48 participants who stopped smoking, white blood cell count (-0.7+/-1.2 x 10(9)/L; P<.001) and fibrinogen (-0.6+/-1.5 micromol/L; P<.01) decreased, but there was no significant (P>.1) change in the plasma level of C-reactive protein (median change +0.1; interquartile range -0.2, 0.9 mg/L), intercellular adhesion molecule 1 (+17+/-75 ng/mL), or CD40 ligand (+0.4+/-2.1 ng/mL). Most of the individual variation in inflammatory marker levels was unrelated to changes in smoking habit.

The effects of exercise and nicotine replacement therapy on smoking rates in women.

PURPOSE: To examine the individual effects of supervised and intensive exercise as well as the combined effects of exercise and nicotine replacement therapy (NRT) on (a) smoking cessation and reduction rates and (b) psychological and physiological processes during withdrawal. METHODS: One-hundred and forty-two inactive female smokers were randomised into the following four groups: exercise+nicotine patch; exercise+no nicotine patch; cognitive behavior therapy (CBT)+nicotine patch and CBT+no nicotine patch. Smoking abstinence (verified by saliva cotinine and expired carbon monoxide), cessation self-efficacy, and physical fitness and body weight were assessed at baseline (week 1), quit date (week 6), program termination (week 12), and 3- and 12-month follow-up. RESULTS: There were significant differences in a 7-day point prevalence but not continuous abstinence rates between treatment groups across targeted end points. Consistently higher cessation rates were seen when NRT was added to both treatment programs. Compared with CBT participants, exercise participants had significantly increased functional exercise capacity and had gained significantly less weight during program end points but these differences did not hold at a 12-month follow-up. Compared with exercise participants, CBT participants felt greater cessation efficacy and reported greater knowledge, coping and support resources across all end points. CONCLUSIONS: Exercise combined with NRT facilitates smoking cessation, improves functional exercise capacity, and delays weight gain in women smokers. We recommend that physicians and health care professionals recommend exercise and NRT together for highly motivated women interested in quitting smoking.

Effects of exercise training on 5 inflammatory markers associated with cardiovascular risk.

BACKGROUND: Cross-sectional studies suggest that regular exercise has anti-inflammatory effects, leading to lower levels of several proatherogenic inflammatory markers. However, this has yet to be confirmed by randomized prospective trials. We performed a randomized controlled trial to assess whether exercise training decreases levels of 5 inflammatory markers linked to future cardiovascular risk: white blood cell count, fibrinogen, C-reactive protein, soluble intercellular adhesion molecule 1, and soluble CD40 ligand. METHODS: One hundred fifty-two healthy female smokers were randomized to either 12 weeks of exercise training or health education as part of a smoking cessation program. Smoking was held steady for the first 6 weeks, and thereafter, smoking cessation was actively attempted. One hundred four participants completed 6 weeks, and 88 completed 12 weeks. Fitness and circulating inflammatory marker levels were measured at baseline, 6 weeks, and 12 weeks. To avoid potential confounding from changes in smoking exposure during the second 6 weeks of the trial, the primary end point was change in inflammatory marker levels from baseline to 6 weeks. Change in inflammatory markers from baseline to 12 weeks was a secondary end point. RESULTS: At baseline, greater physical fitness was associated with lower white blood cell, fibrinogen, and C-reactive protein levels, but these associations were not statistically significant after adjusting for body mass index (P > .1 for all). Fitness improved significantly in the exercise group at both 6 and 12 weeks. However, there were no differences in levels of any inflammatory marker between the exercise and control groups at either 6 weeks (primary end point) or 12 weeks (secondary end point) (P > .05 for all comparisons). CONCLUSION: In female smokers, baseline associations between fitness and inflammatory markers were largely attributable to differences in body fat; regular exercise did not reduce levels of any of the inflammatory markers studied despite a significant improvement in fitness at both 6 and 12 weeks.