Exercise for patients with chronic kidney disease: from cells to systems to function.

Chronic kidney disease (CKD) is among the leading causes of death and disability, affecting an estimated 800 million adults globally. The underlying pathophysiology of CKD is complex creating challenges to its management. Primary risk factors for the development and progression of CKD include diabetes mellitus, hypertension, age, obesity, diet, inflammation, and physical inactivity. The high prevalence of diabetes and hypertension in patients with CKD increases the risk for secondary consequences such as cardiovascular disease and peripheral neuropathy. Moreover, the increased prevalence of obesity and chronic levels of systemic inflammation in CKD have downstream effects on critical cellular functions regulating homeostasis. The combination of these factors results in the deterioration of health and functional capacity in those living with CKD. Exercise offers protective benefits for the maintenance of health and function with age, even in the presence of CKD. Despite accumulating data supporting the implementation of exercise for the promotion of health and function in patients with CKD, a thorough description of the responses and adaptations to exercise at the cellular, system, and whole body levels is currently lacking. Therefore, the purpose of this review is to provide an up-to-date comprehensive review of the effects of exercise training on vascular endothelial progenitor cells at the cellular level; cardiovascular, musculoskeletal, and neural factors at the system level; and physical function, frailty, and fatigability at the whole body level in patients with CKD.

Impact of Cardiorespiratory Fitness on Mortality in Black Male Veterans With Resistant Systemic Hypertension.

Patients with resistant systemic hypertension have poorer outcomes than nonresistant hypertensives. The purpose of this study was to evaluate the association between cardiorespiratory fitness and all-cause mortality in black male Veterans with resistant systemic hypertension. Patients were identified from a cohort undergoing exercise tolerance test at the department of Veterans Affairs Medical Center in Washington, DC. Patients were divided into 4 cardiorespiratory fitness categories based on age-specific peak metabolic equivalents achieved on a standard Bruce protocol. Multivariate Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality across all fitness categories. A total of 1,276 patients out of 9,068 hypertensives had resistant hypertension defined as systolic and/or diastolic blood pressure >140 and/or >90 mm Hg, respectively, on 3 antihypertensive medications, one of which was a diuretic or use of >4 antihypertensive medications. During a follow-up of 9.5 ± 4.2 years, an inverse association was observed between cardiorespiratory fitness and all-cause mortality in patients with resistant hypertension. Compared with the least-fit group, mortality was reduced by 21% in the low-fit group (HR 0.79, CI 0.60 to 1.05; p value: 0.280), 36% in the moderate-fit group (HR 0.64, CI 0.48 to 0.87; p value 0.001), and 62% in the high-fit group (HR 0.38, CI 0.25 to 0.56; p value <0.001). In conclusion, an inverse association was observed between the level of cardiorespiratory fitness and all-cause mortality in patients with resistant systemic hypertension. Compared with the least-fit referent group, the high-fit group had a significant 62% lower risk of all-cause mortality.

The Interaction of Cardiorespiratory Fitness With Obesity and the Obesity Paradox in Cardiovascular Disease.

Overweight and obesity are well-established risk factors for most cardiovascular diseases (CVD), including coronary heart disease (CHD), heart failure (HF), and atrial fibrillation. Despite the strong link between excess adiposity and risk of CVD, growing evidence has demonstrated an obesity paradox in patients with CVD. This phenomenon is characterized by a better prognosis in overweight and mildly obese CVD patients than their leaner counterparts. Moreover, the worst outcomes are often incurred by underweight CVD patients, followed by those of normal weight or severely obese. The obesity paradox is now a well-established phenomenon across different types of CVD, and it occurs regardless of age and ethnicity of patients, and severity of CVD. Physical inactivity and low cardiorespiratory fitness (CRF) have long been recognized as major risk factors for CVD. In contrast, high levels of physical activity (PA) and CRF largely neutralize the adverse effects of excess adiposity and other traditional CVD risk factors, including hypertension, metabolic syndrome, and type-2 diabetes. Higher CRF also results in better CVD outcomes across different BMI groups and significantly alters the obesity paradox in patients with HF and CHD. Prognostic benefits of overweight/obesity tend to be limited to unfit patients with HF and CHD, and the obesity paradox usually disappears with improved levels of CRF. Nevertheless, increased PA and exercise training, to maintain or improve CRF, are effective, safe, and proven strategies for primary and secondary prevention of CVD in all weight groups. In this review, we discuss the current concepts of individual and combined contributions of fatness and fitness to CVD risk and prognosis. We then examine the influence of fitness on the obesity paradox in individuals with CVD.

Impact of Changes in Cardiorespiratory Fitness on Hypertension, Dyslipidemia and Survival: An Overview of the Epidemiological Evidence.

Over the last fifty years, cardiorespiratory fitness (CRF) has been firmly established as an important risk factor for cardiovascular disease (CVD) and all-cause mortality. Mounting evidence supports a strong and inverse association between baseline CRF and the risk of developing hypertension (HTN) and dyslipidemia. Accumulating evidence also suggests that improving or maintaining a certain level of CRF over time leads to lower incidence of HTN and dyslipidemia and improves survival. These findings are promising, with significant public health importance, and warrant further evaluation to elucidate the role of longitudinal changes in CRF during the lifespan on CVD morbidity and mortality, as well as all-cause survival.

Longitudinal Patterns of Cardiorespiratory Fitness Predict the Development of Hypertension Among Men and Women.

BACKGROUND: Most of the existing literature has linked a baseline cardiorespiratory fitness or change between baseline and one follow-up measurement of cardiorespiratory fitness to hypertension. The purpose of the study is to assess the association between longitudinal patterns of cardiorespiratory fitness changes with time and incident hypertension in adult men and women. METHODS: Participants were aged 20 to 82 years, were free of hypertension during the first 3 examinations, and received at least 4 preventive medical examinations at the Cooper Clinic in Dallas, Texas, from 1971 to 2006. They were classified into 1 of 5 groups based on all of the measured cardiorespiratory fitness values (in metabolic equivalents) during maximal treadmill tests. Logistic regression was used to compute odds ratios and 95% confidence intervals. RESULTS: Among 4932 participants (13% women), 1954 developed hypertension. After controlling for baseline potential confounders, follow-up duration, and number of follow-up visits, odds ratios (95% confidence intervals) for hypertension were 1.00 for the decreasing group (referent), 0.64 (0.52-0.80) for the increasing group, 0.89 (0.70-1.12) for the bell-shape group, 0.78 (0.62-0.98) for the U-shape group, and 0.83 (0.69-1.00) for the inconsistent group. The general pattern of the association was consistent regardless of participants' baseline cardiorespiratory fitness or body mass index levels. CONCLUSIONS: An increasing pattern of cardiorespiratory fitness provides the lowest risk of hypertension in this middle-aged relatively healthy population. Identifying specific pattern(s) of cardiorespiratory fitness change may be important for determining associations with comorbidity, such as hypertension.

Cardiorespiratory Fitness and Incidence of Major Adverse Cardiovascular Events in US Veterans: A Cohort Study.

OBJECTIVE: To assess the association between exercise capacity and the risk of major adverse cardiovascular events (MACEs). PATIENTS AND METHODS: A symptom-limited exercise tolerance test was performed to assess exercise capacity in 20,590 US veterans (12,975 blacks and 7615 whites; mean ± SD age, 58.2±11.0 years) from the Veterans Affairs medical centers in Washington, District of Columbia, and Palo Alto, California. None had a history of MACE or evidence of ischemia at the time of or before their exercise tolerance test. We established quintiles of cardiorespiratory fitness (CRF) categories based on age-specific peak metabolic equivalents (METs) achieved. We also defined the age-specific MET level associated with no risk for MACE (hazard ratio [HR], 1.0) and formed 4 additional CRF categories based on METs achieved below (least fit and low fit) and above (moderately fit and highly fit) that level. Multivariate Cox models were used to estimate HR and 95% CIs for mortality across fitness categories. RESULTS: During follow-up (median, 11.3 years; range, 0.3-33.0 years), 2846 individuals experienced MACEs. The CRF-MACE association was inverse and graded. The risk for MACE declined precipitously for those with a CRF level of 6.0 METs or higher. When considering CFR categories based on the age-specific MET threshold, the risk increased for those in the 2 CFR categories below that threshold (HR, 1.95; 95% CI, 1.73-2.21 and HR, 1.41; 95% CI, 1.27-1.56 for the least-fit and low-fit individuals, respectively) and decreased for those above it (HR, 0.77; 95% CI, 0.68-0.87 and HR, 0.57; 95% CI, 0.48-0.67 for moderately fit and highly fit, respectively). CONCLUSION: Increased CRF is inversely and independently associated with the risk for MACE. When an age-specific MET threshold was defined, the risk for MACE increased significantly for those below that threshold and decreased for those above it (P<.001).

The Impact of Cardiorespiratory Fitness Levels on the Risk of Developing Atherogenic Dyslipidemia.

BACKGROUND: Low cardiorespiratory fitness has been established as a risk factor for cardiovascular-related morbidity. However, research about the impact of fitness on lipid abnormalities, including atherogenic dyslipidemia, has produced mixed results. The purpose of this investigation is to examine the influence of baseline fitness and changes in fitness on the development of atherogenic dyslipidemia. METHODS: All participants completed at least 3 comprehensive medical examinations performed by a physician that included a maximal treadmill test between 1976 and 2006 at the Cooper Clinic in Dallas, Texas. Atherogenic dyslipidemia was defined as a triad of lipid abnormalities: low high-density-lipoprotein cholesterol ([HDL-C] <40 mg/dL), high triglycerides ([TGs] ≥200 mg/dL), and high low-density-lipoprotein cholesterol ([LDL-C] ≥160 mg/dL). RESULTS: A total of 193 participants developed atherogenic dyslipidemia during an average of 8.85 years of follow-up. High baseline fitness was protective against the development of atherogenic dyslipidemia in comparison with those with low fitness (odds ratio [OR] 0.57; 95% confidence interval [CI], 0.37-0.89); however, this relationship became nonsignificant after controlling for baseline HDL-C, LDL-C, and TG levels. Participants who maintained fitness over time had lower odds of developing atherogenic dyslipidemia than those with a reduction in fitness (OR 0.56; 95% CI, 0.34-0.91) after adjusting for baseline confounders and changes in known risk factors. CONCLUSIONS: High fitness at baseline and maintenance of fitness over time are protective against the development of atherogenic dyslipidemia.

The effect of cardiorespiratory fitness on age-related lipids and lipoproteins.

BACKGROUND: Evidence on the effect of cardiorespiratory fitness (CRF) on age-related longitudinal changes of lipids and lipoproteins is scarce. OBJECTIVES: This study sought to assess the longitudinal aging trajectory of lipids and lipoproteins for the life course in adults and to determine whether CRF modifies the age-associated trajectory of lipids and lipoproteins. METHODS: Data came from 11,418 men, 20 to 90 years of age, without known high cholesterol, high triglycerides, cardiovascular disease, and cancer at baseline and during follow-up from the Aerobics Center Longitudinal Study. There were 43,821 observations spanning 2 to 25 health examinations (mean 3.5 examinations) between 1970 and 2006. CRF was quantified by a maximal treadmill exercise test. Marginal models using generalized estimating equations were applied. RESULTS: Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides, and non-high-density lipoprotein cholesterol (non-HDL-C) presented similar inverted U-shaped quadratic trajectories with aging: gradual increases were noted until age mid-40s to early 50s, with subsequent declines (all p < 0.0001). Compared with men with higher CRF, those with lower CRF developed abnormal values earlier in life: TC (≥200 mg/dl), LDL-C (≥130 mg/dl), non-HDL-C (≥160 mg/dl), and triglycerides/HDL-C ratio (≥3.0). Notably, abnormal values for TC and LDL-C in men with low CRF were observed around 15 years earlier than in those with high CRF. After adjusting for time-varying covariates, a significant interaction was found between age and CRF in each trajectory, indicating that CRF was more strongly associated with the aging trajectories of lipids and lipoproteins in young to middle-age men than in older men. CONCLUSIONS: Our investigation reveals a differential trajectory of lipids and lipoproteins with aging according to CRF in healthy men and suggests that promoting increased CRF levels may help delay the development of dyslipidemia.

Relationship of Physical Activity and Healthy Eating with Mortality and Incident Heart Failure among Community-Dwelling Older Adults with Normal Body Mass Index.

AIMS: Normal body mass index (BMI) is associated with lower mortality and may be achieved by physical activity (PA), healthy eating (HE), or both. We examined the association of PA and HE with mortality and incident heart failure (HF) among 2040 community-dwelling older adults aged ≥ 65 years with baseline BMI 18.5 to 24.99 kg/m2 during 13 years of follow-up in Cardiovascular Health Study. METHODS AND RESULTS: Baseline PA was defined as ≥500 weekly metabolic equivalent task-minutes (MET-minutes) and HE as ≥5 daily servings of vegetable and fruit intake. Participants were categorized into 4 groups: (1) PA-/HE- (n=384); (2) PA+/HE- (n=992); (3) PA-/HE+ (n=162); and (4) PA+/HE+ (n=502). Participants had a mean age of 74 (±6) years, mean BMI of 22.6 (±1.5) kg/m2, 61% were women, and 4% African American. Compared with PA-/HE-, age-sex-race-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality for PA-/HE+, PA+/HE-, and PA+/HE+ groups were 0.96 (0.76-1.21), 0.61 (0.52-0.71) and 0.62 (0.52-0.75), respectively. These associations remained unchanged after multivariable adjustment and were similar for cardiovascular and non-cardiovascular mortalities. Respective demographic-adjusted HRs (95% Cis) for incident HF among 1954 participants without baseline HF were 1.21 (0.81-1.81), 0.71 (0.54-0.94) and 0.71 (0.51-0.98). These later associations lost significance after multivariable-adjustment. CONCLUSION: Among community-dwelling older adults with normal BMI, physical activity, regardless of healthy eating, was associated with lower risk of mortality and incident HF, but healthy eating had no similar protective association in this cohort.

Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study.

BACKGROUND: Statins are commonly prescribed for management of dyslipidaemia and cardiovascular disease. Increased fitness is also associated with low mortality and is recommended as an essential part of promoting health. However, little information exists about the combined effects of fitness and statin treatment on all-cause mortality. We assessed the combined effects of statin treatment and fitness on all-cause mortality risk. METHODS: In this prospective cohort study, we included dyslipidaemic veterans from Veterans Affairs Medical Centers in Palo Alto, CA, and Washington DC, USA, who had had an exercise tolerance test between 1986, and 2011. We assigned participants to one of four fitness categories based on peak metabolic equivalents (MET) achieved during exercise test and eight categories based on fitness status and statin treatment. The primary endpoint was all-cause mortality adjusted for age, body-mass index, ethnic origin, sex, history of cardiovascular disease, cardiovascular drugs, and cardiovascular risk factors. We assessed mortality from Veteran's Affairs' records on Dec 31, 2011. We compared groups with Cox proportional hazard model. FINDINGS: We assessed 10,043 participants (mean age 58·8 years, SD 10·9 years). During a median follow-up of 10·0 years (IQR 6·0-14·2), 2318 patients died, with an average yearly mortality rate of 22 deaths per 1000 person-years. Mortality risk was 18·5% (935/5046) in people taking statins versus 27·7% (1386/4997) in those not taking statins (p<0·0001). In patients who took statins, mortality risk decreased as fitness increased; for highly fit individuals (>9 MET; n=694), the hazard ratio (HR) was 0·30 (95% CI 0·21-0·41; p<0·0001) compared with least fit (≤5 METs) patients (HR 1; n=1060). For those not treated with statins, the HR for least fit participants (n=1024) was 1·35 (95% CI 1·17-1·54; p<0·0001) and progressively decreased to 0·53 (95% CI 0·44-0·65; p<0·0001) for those in the highest fitness category (n=1498). INTERPRETATION: Statin treatment and increased fitness are independently associated with low mortality among dyslipidaemic individuals. The combination of statin treatment and increased fitness resulted in substantially lower mortality risk than either alone, reinforcing the importance of physical activity for individuals with dyslipidaemia. FUNDING: None.

Obesity paradox and cardiorespiratory fitness in 12,417 male veterans aged 40 to 70 years.

OBJECTIVE: To evaluate the influence of cardiorespiratory fitness (fitness) on the obesity paradox in middle-aged men with known or suspected coronary artery disease. PATIENTS AND METHODS: This study consists of 12,417 men aged 40 to 70 years (44% African American) who were referred for exercise testing at the Veterans Affairs Medical Centers in Washington, DC, or Palo Alto, CA (between January 1, 1983, and June 30, 2007). Fitness was quantified as metabolic equivalents achieved during a maximal exercise test and was categorized for analysis as low, moderate, and high (defined as <5, 5-10, and >10 metabolic equivalents, respectively). Adiposity was defined by body mass index (BMI) according to standard clinical guidelines. Separate and combined associations of fitness and adiposity with all-cause mortality were assessed by Cox proportional hazards analyses. RESULTS: We recorded 2801 deaths during a mean+/-SD follow-up of 7.7+/-5.3 years. Multivariate hazard ratios (95% confidence interval) for all-cause mortality, with normal weight (BMI, 18.5-24.9 kg/m2) used as the reference group, were 1.9 (1.5-2.3), 0.7 (0.7-0.8), 0.7 (0.6-0.7), and 1.0 (0.8-1.1) for BMIs of less than 18.5, 25.0 to 29.9, 30.0 to 34.9, and 35.0 or more kg/m2, respectively. Compared with highly fit normal-weight men, underweight men with low fitness had the highest (4.5 [3.1-6.6]) and highly fit overweight men the lowest (0.4 [0.3-0.6]) mortality risk of any subgroup. Overweight and obese men with moderate fitness had mortality rates similar to those of the highly fit normal-weight reference group. CONCLUSION: Fitness altered the obesity paradox. Overweight and obese men had increased longevity only if they registered high fitness.

Physiological alterations to detraining following prolonged combined strength and aerobic training in cardiac patients.

BACKGROUND: The purpose of the present study was to assess the training and detraining effects on physiological parameters resulting from a combined strength and aerobic exercise programme in patients with coronary artery disease. DESIGN AND METHODS: Thirty male coronary artery disease patients were randomly assigned to an exercise (n = 16) and control group (n = 14). Patients in the exercise group participated in a supervised exercise programme for 8 months and were followed for 3 months after training cessation. The programme consisted of two sessions of circuit weight training and two sessions of aerobic training. Cardiopulmonary testing and muscular strength were assessed at baseline and after 4 and 8 months of training as well as after 3 months of detraining. RESULTS: The exercise training programme resulted in significant improvement in cardiorespiratory fitness (VO2peak 15.4% and exercise time 14%) after 8 months. Muscular strength also increased significantly in all exercises by an average of 28% (upper body 25.5% and lower body 35.4%). Three months of detraining, however, resulted in a 10% regression in VO2peak, 6.7% in exercise time, 12% in upper body strength and 15.7% in lower body strength. CONCLUSIONS: The above results indicate that a significant part of the favourable adaptations obtained after prolonged training is practically lost within 3 months of detraining. Therefore, patients with coronary artery disease should follow a systematic exercise programme throughout life in order to improve cardiovascular function, muscular strength and ameliorate their health status.

The association between physical activity and the development of acute coronary syndromes in treated and untreated hypertensive subjects.

The objective of this study was to evaluate the effect of physical activity on the risk of coronary events in different groups of hypertensive patients. During 2000-2001, 848 patients hospitalized for a first event of coronary heart disease and 1078 hospitalized controls without any suspicion of coronary heart disease, paired by sex and age, were randomly selected from all Greek regions. A total of 418 (49%) of the patients and 303 (28%) of the controls were classified as hypertensives, while 88 (21%) of the hypertensive patients and 88 (29%) of the hypertensive controls, reported regular leisure-time physical activity. Compared to physical inactivity, the analysis showed that light to moderate physical activity was associated with a reduction by 12% of the coronary risk in controlled hypertensive subjects (p=0.03), by 9% (p=0.04) in hypertensives who were untreated or unaware of their condition, and by 5% (p=0.087) in uncontrolled hypertensives. The practice of regular physical activity seems to be associated with lower coronary risk in various groups of hypertensives. However, these data cannot prove causality, and prospective studies will be necessary to confirm or refute the authors findings.

Determinants of exercise blood pressure response in normotensive and hypertensive women: role of cardiorespiratory fitness.

PURPOSE: Exaggerated blood pressure (BP) response during physical exertion is associated with increased risk for cardiovascular events. Furthermore, it may be the predisposing factor for myocardial infarction triggered by physical exertion. The authors have shown that systolic BP achieved after 6 minutes of exercise is the strongest predictor of left ventricular hypertrophy. Furthermore, a 37 mm Hg increase in systolic BP above resting BP at 6 minutes of exercise was the threshold for left ventricular hypertrophy. The purpose of this study was to determine predictors of exercise BP response in normotensive and hypertensive women. METHODS: An exercise tolerance test (Bruce) was performed by 1411 normotensive (resting BP < 140/90 mm Hg) and hypertensive (resting BP > or = 140/90 mm Hg) women. These women were faculty, students, and staff at the University of Maryland, College Park, Maryland, and the George Washington University Medical Center, as well as patients undergoing a routine exercise tolerance test at West Coast Cardiology, Pinellas Park, Florida. Two fitness categories (low-fit and high-fit) were established on the basis of treadmill time to exhaustion adjusted for age. RESULTS: Significant associations were observed among the 6-minute exercise BP and age, body mass index, resting systolic and diastolic BP, heart rate, and exercise time to exhaustion. In a stepwise multiple-regression analysis, the determinants of BP after 6 minutes of exercise were resting systolic BP and treadmill time to exhaustion (R2 = 0.36) for normotensive women and treadmill time to exhaustion and resting systolic BP (R2 = 0.30) for hypertensive women. When fitness categories were contrasted, low-fit women in both the normotensive and hypertensive categories had higher BP and rate-pressure product after 6 minutes of exercise than the high-fit women (P <.05). CONCLUSIONS: Resting systolic BP and cardiorespiratory fitness are determinants of a submaximal exercise BP response for both hypertensive and normotensive women. Low cardiorespiratory fitness is associated with a higher BP response during submaximal exercise, suggesting that increased fitness may attenuate this abnormal rise in BP. Thus, low- to moderate-intensity physical activities for most days of the week should be encouraged for all women to increase cardiorespiratory fitness. This is likely to attenuate an abnormal rise in systolic BP that may occur during routine daily activities and protect against the associated health consequences.

Exercise Training and Blood Pressure Control in Patients With Hypertension.

Several randomized, well controlled exercise intervention studies have shown that regularly performed aerobic exercise significantly lowers blood pressure in patients with essential hypertension. Mild to moderate intensity exercise may be more effective in lowering blood pressure than higher intensity exercises. Three or more sessions per week of 30-60 minutes per session are required to achieve optimal results. Such exercise is also safe and effective in lowering blood pressure in treated patients with severe hypertension and left ventricular hypertrophy (LVH). A significant reduction in blood pressure and LVH regression may be achieved in these patients even with substantial reduction in antihypertensive medication. The safety and efficacy of mild to moderate exercise has positive clinical implications for all hypertensive patients. Exercise induced reductions in resting blood pressure and the prevention of an abnormal rise in blood pressure during physical exertion can lead to fewer cardiovascular events. It may also reduce antihypertensive medication requirements, cost, medication related side effects, and improve quality of life. (c)1999 by Le Jacq Communications, Inc.