Mark J. Haykowsky

Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial

IMPORTANCE More than 80% of patients with heart failure with preserved ejection fraction (HFPEF), the most common form of heart failure among older persons, are overweight or obese. Exercise intolerance is the primary symptom of chronic HFPEF and a major determinant of reduced quality of life (QOL). OBJECTIVE To determine whether caloric restriction (diet) or aerobic exercise training (exercise) improves exercise capacity and QOL in obese older patients with HFPEF. DESIGN, SETTING, AND PARTICIPANTS Randomized, attention-controlled, 2 × 2 factorial trial conducted from February 2009 through November 2014 in an urban academic medical center. Of 577 initially screened participants, 100 older obese participants (mean [SD]: age, 67 years [5]; body mass index, 39.3 [5.6]) with chronic, stable HFPEF were enrolled (366 excluded by inclusion and exclusion criteria, 31 for other reasons, and 80 declined participation). INTERVENTIONS Twenty weeks of diet, exercise, or both; attention control consisted of telephone calls every 2 weeks. MAIN OUTCOMES AND MEASURES Exercise capacity measured as peak oxygen consumption (V̇O2, mL/kg/min; co-primary outcome) and QOL measured by the Minnesota Living with Heart Failure (MLHF) Questionnaire (score range: 0-105, higher scores indicate worse heart failure-related QOL; co-primary outcome). RESULTS Of the 100 enrolled participants, 26 participants were randomized to exercise; 24 to diet; 25 to exercise + diet; 25 to control. Of these, 92 participants completed the trial. Exercise attendance was 84% (SD, 14%) and diet adherence was 99% (SD, 1%). By main effects analysis, peak V̇O2 was increased significantly by both interventions: exercise, 1.2 mL/kg body mass/min (95% CI, 0.7 to 1.7), P < .001; diet, 1.3 mL/kg body mass/min (95% CI, 0.8 to 1.8), P < .001. The combination of exercise + diet was additive (complementary) for peak V̇O2 (joint effect, 2.5 mL/kg/min). There was no statistically significant change in MLHF total score with exercise and with diet (main effect: exercise, -1 unit [95% CI, -8 to 5], P = .70; diet, -6 units [95% CI, -12 to 1], P = .08). The change in peak V̇O2 was positively correlated with the change in percent lean body mass (r = 0.32; P = .003) and the change in thigh muscle:intermuscular fat ratio (r = 0.27; P = .02). There were no study-related serious adverse events. Body weight decreased by 7% (7 kg [SD, 1]) in the diet group, 3% (4 kg [SD, 1]) in the exercise group, 10% (11 kg [SD, 1] in the exercise + diet group, and 1% (1 kg [SD, 1]) in the control group. CONCLUSIONS AND RELEVANCE Among obese older patients with clinically stable HFPEF, caloric restriction or aerobic exercise training increased peak V̇O2, and the effects may be additive. Neither intervention had a significant effect on quality of life as measured by the MLHF Questionnaire. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00959660.

Modulation of Anthracycline-Induced Cardiotoxicity by Aerobic Exercise in Breast Cancer Current Evidence and Underlying Mechanisms

Anthracycline-containing chemotherapy (eg, doxorubicin) is well known to cause dose-dependent, progressive cardiac damage clinically manifest as decreased left ventricular (LV) ejection fraction and, ultimately, heart failure (HF) (Table 1).1,2 Unfortunately, the only clinically accepted method to minimize injury is dose modification and/or therapy discontinuation.3 An important current challenge in breast cancer management is therefore to maximize the benefits of doxorubicin while minimizing cardiac damage. Identification and examination of new interventions to prevent and/or treat doxorubicin-induced cardiotoxicity are urgently required. View this table: Table 1. Stages of Doxorubicin-Induced Cardiotoxicity Aerobic exercise is a nonpharmacological therapy that promises to attenuate doxorubicin-induced cardiotoxicity. Aerobic exercise is well documented to improve systolic and diastolic function and attenuate pathological cardiac remodeling, resulting in improved exercise tolerance and resistance to fatigue during exertion in patients with HF.4,5 The cardioprotective properties of aerobic exercise in the context of doxorubicin have, in contrast, received scant attention. It is not generally used in cancer patients despite its lack of “side effects” and the paucity of alternative strategies to prevent/treat doxorubicin-associated cardiac damage. As a first step in the possible use of exercise in cancer patients, we reviewed the mechanisms of doxorubicin-induced cardiotoxicity and the available evidence supporting the utility of aerobic exercise to prevent/treat cardiac injury. We also explored the molecular mechanisms that may underlie the cardioprotective properties of aerobic exercise. These findings have implications for future research regarding the application and effectiveness of exercise and doxorubicin treatment in humans. The mechanisms underlying the antitumor function of anthracyclines have been described previously.6–8 Among the proposed mechanisms of cardiac injury, doxorubicin-induced generation of reactive oxygen species (ROS)9,10 is a central mediator of numerous direct and indirect cardiac adverse consequences (for review, see Minotti et al11). In the present report, we …

Adjuvant Trastuzumab Induces Ventricular Remodeling Despite Aerobic Exercise Training

Purpose: To examine the effect of aerobic training in mitigating trastuzumab-mediated left ventricular (LV) remodeling in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Experimental Design: Seventeen women (53 ± 7 years) with HER2-positive breast cancer did aerobic training during the first 4 months of adjuvant trastuzumab. Peak oxygen consumption and magnetic resonance imaging assessment of LV volumes, mass, and rest and peak (dobutamine stress) ejection fraction were assessed before and after 4 months of trastuzumab. Results: Participants attended 59% ± 32% of prescribed exercise sessions at 78% ± 6% of peak heart rate. Peak exercise heart rate, systolic and diastolic blood pressure, power output, and oxygen consumption were not different after training (all P-values > 0.05). Exercise adherence predicted change in peak oxygen consumption (r = 0.77; P = 0.000). Resting end-diastolic (pre: 120 ± 23 mL versus post: 133 ± 16 mL) and end-systolic volumes (pre: 44 ± 12 mL versus post: 55 ± 11 mL) and mass (pre: 108 ± 21 g versus post: 114 ± 18 g) increased, whereas ejection fraction (pre: 64% ± 4% versus post: 59% ± 4%) decreased from baseline to post-intervention (all P-values < 0.05). Peak ejection fraction was lower after 4 months (pre: 79 ± 4 versus post: 76 ± 6%; P = 0.087). Conclusion: Initiation of adjuvant trastuzumab therapy is associated with LV cavity dilation and reduced ejection fraction despite aerobic exercise training. The long-term consequences of trastuzumab-induced LV remodeling and the means to prevent LV dysfunction require further study.

Carotid Arterial Stiffness and Its Relationship to Exercise Intolerance in Older Patients With Heart Failure and Preserved Ejection Fraction

Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance; however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond what occurs with normal aging and that this contributes to their severe exercise intolerance. Sixty-nine patients ≥60 years of age with HFpEF and 62 healthy volunteers (24 young healthy subjects ⩽30 years and 38 older healthy subjects ≥60 years old) were examined. Carotid arterial stiffness was assessed using high-resolution ultrasound, and peak exercise oxygen consumption was measured using expired gas analysis. Peak exercise oxygen consumption was severely reduced in the HFpEF patients compared with older healthy subjects (14.1±2.9 versus 19.7±3.7 mL/kg per minute; P<0.001) and in both was reduced compared with young healthy subjects (32.0±7.2 mL/kg per minute; both P<0.001). In HFpEF compared with older healthy subjects, carotid arterial distensibility was reduced (0.97±0.45 versus 1.33±0.55×10–3 mm Hg−1; P=0.008) and Young’s elastic modulus was increased (1320±884 versus 925±530 kPa; P<0.02). Carotid arterial distensibility was directly (0.28; P=0.02) and Young’s elastic modulus was inversely (–0.32; P=0.01) related to peak exercise oxygen consumption. Carotid arterial distensibility is decreased in HFpEF beyond the changes attributed to normal aging and is related to peak exercise oxygen consumption. This supports the hypothesis that increased arterial stiffness contributes to exercise intolerance in HFpEF and is a potential therapeutic target.

Opioid prescriptions in canadian workers' compensation claimants: prescription trends and associations between early prescription and future recovery.

Study Design. Historical cohort study. Objective. We investigated the prescription of opioids in injured Canadian workers to determine recent trends in use and the association between early prescription and future recovery. Summary of Background Data. Opioid analgesia is effective for reducing chronic nonmalignant pain, and opioid prescriptions for musculoskeletal pain seem to have increased over the past years. However, recent evidence indicates early opioid use may be associated with delayed recovery in patients with back pain. Methods. Data were extracted from the Alberta Workers’ Compensation Board administrative database, and information was obtained on all time loss claims for sprains, strains, fractures, dislocations, amputations, or burns between January 1, 2000 and December 31, 2005. Information on all narcotic prescriptions was obtained along with demographic data and duration of time loss benefits. Injury severity was controlled for via nature of injury coding. Analysis included multivariable logistic and Cox regression. Results. Data were obtained for 137,175 subjects. The majority were males (∼70%) with back sprains (∼35%), and a mean age of 37 years. Between the years 2000 and 2005, all opioid prescriptions within the first year of claim decreased from 11.4% of claimants to 8.3%. Older males with fractures, dislocations, or amputations were more likely to receive narcotics. Claimants receiving early opioid prescriptions experienced delayed suspension of benefits. However, this association was also seen in claimants prescribed early non-narcotic analgesics. Discussion. Prescriptions for opioid analgesia appear to be decreasing within workers’ compensation claimants in Alberta, Canada. As expected, claimants with more severe injuries were more likely to receive opioids. An association was observed between early opioid prescription and delayed recovery, however, this is likely explained by pain severity or other unmeasured confounders.

Exercise intolerance in heart failure with preserved ejection fraction: more than a heart problem

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in older adults, and is increasing in prevalence as the population ages. Furthermore, HFpEF is increasing out of proportion to HF with reduced EF (HFrEF), and its prognosis is worsening while that of HFrEF is improving. Despite the importance of HFpEF, our understanding of its pathophysiology is incomplete, and optimal treatment remains largely undefined. A cardinal feature of HFpEF is reduced exercise tolerance, which correlates with symptoms as well as reduced quality of life. The traditional concepts of exercise limitations have focused on central dysfunction related to poor cardiac pump function. However, the mechanisms are not exclusive to the heart and lungs, and the understanding of the pathophysiology of this disease has evolved. Substantial attention has focused on defining the central versus peripheral mechanisms underlying the reduced functional capacity and exercise tolerance among patients with HF. In fact, physical training can improve exercise tolerance via peripheral adaptive mechanisms even in the absence of favorable central hemodynamic function. In addition, the drug trials performed to date in HFpEF that have focused on influencing cardiovascular function have not improved exercise capacity. This suggests that peripheral limitations may play a significant role in HF limiting exercise tolerance, a hallmark feature of HFpEF.

Prioritizing Functional Capacity as a Principal End Point for Therapies Oriented to Older Adults With Cardiovascular Disease: A Scientific Statement for Healthcare Professionals From the American Heart Association

Adults are living longer, and cardiovascular disease is endemic in the growing population of older adults who are surviving into old age. Functional capacity is a key metric in this population, both for the perspective it provides on aggregate health and as a vital goal of care. Whereas cardiorespiratory function has long been applied by cardiologists as a measure of function that depended primarily on cardiac physiology, multiple other factors also contribute, usually with increasing bearing as age advances. Comorbidity, inflammation, mitochondrial metabolism, cognition, balance, and sleep are among the constellation of factors that bear on cardiorespiratory function and that become intricately entwined with cardiovascular health in old age. This statement reviews the essential physiology underlying functional capacity on systemic, organ, and cellular levels, as well as critical clinical skills to measure multiple realms of function (eg, aerobic, strength, balance, and even cognition) that are particularly relevant for older patients. Clinical therapeutic perspectives and patient perspectives are enumerated to clarify challenges and opportunities across the caregiving spectrum, including patients who are hospitalized, those managed in routine office settings, and those in skilled nursing facilities. Overall, this scientific statement provides practical recommendations and vital conceptual insights.

High Intensity Interval Training for Maximizing Health Outcomes

Regular physical activity and exercise training are important actions to improve cardiorespiratory fitness and maintain health throughout life. There is solid evidence that exercise is an effective preventative strategy against at least 25 medical conditions, including cardiovascular disease, stroke, hypertension, colon and breast cancer, and type 2 diabetes. Traditionally, endurance exercise training (ET) to improve health related outcomes has consisted of low- to moderate ET intensity. However, a growing body of evidence suggests that higher exercise intensities may be superior to moderate intensity for maximizing health outcomes. The primary objective of this review is to discuss how aerobic high-intensity interval training (HIIT) as compared to moderate continuous training may maximize outcomes, and to provide practical advices for successful clinical and home-based HIIT.

Effect of acute high-intensity interval exercise on postexercise biventricular function in mild heart failure

We studied the acute effect of high-intensity interval exercise on biventricular function using cardiac magnetic resonance imaging in nine patients [age: 49 ± 16 yr; left ventricular (LV) ejection fraction (EF): 35.8 ± 7.2%] with nonischemic mild heart failure (HF). We hypothesized that a significant impairment in the immediate postexercise end-systolic volume (ESV) and end-diastolic volume (EDV) would contribute to a reduction in EF. We found that immediately following acute high-intensity interval exercise, LV ESV decreased by 6% and LV systolic annular velocity increased by 21% (both P < 0.05). Thirty minutes following exercise (+30 min), there was an absolute increase in LV EF of 2.4% (P < 0.05). Measures of preload, left atrial volume and LV EDV, were reduced immediately following exercise. Similar responses were observed for right ventricular volumes. Early filling velocity, filling rate, and diastolic annular velocity remained unchanged, while LV untwisting rate increased 24% immediately following exercise (P < 0.05) and remained 18% above baseline at +30 min (P < 0.05). The major novel findings of this investigation are 1) that acute high-intensity interval exercise decreases the immediate postexercise LV ESV and increases LV EF at +30 min in patients with mild HF, and this is associated with a reduction in LV afterload and maintenance of contractility, and 2) that despite a reduction in left atrial volume and LV EDV immediately postexercise, diastolic function is preserved and may be modulated by enhanced LV peak untwisting rate. Acute high-intensity interval exercise does not impair postexercise biventricular function in patients with nonischemic mild HF.

Changes in ventricular twist and untwisting with orthostatic stress: endurance athletes versus normally active individuals

Endurance-trained individuals exhibit larger reductions in left ventricular (LV) end-diastolic volume in response to lower body negative pressure (LBNP) compared with normally active individuals. However, the relationship between LV torsion and untwisting and the LV volume response to LBNP in endurance athletes is unknown. Eight endurance-trained athletes [maximal oxygen consumption (VO2max): 66.4+/-7.2 ml.kg(-1).min(-1)] and eight normally active individuals (VO2max: 41.9+/-9.0 ml.kg(-1).min(-1)) (all men) underwent two cardiac magnetic resonance imaging (MRI) assessments, the first during supine rest and the second during -30 mmHg LBNP. Right ventricular (RV) and LV volumes were assessed, myocardial tagging was applied in order to quantify LV peak torsion and peak untwisting rate, and filling rates were measured with phase-contrast MRI. In response to LBNP, endurance-trained individuals had greater reductions in RV and LV end-diastolic volume and stroke volume (P<0.05). Endurance athletes had reduced untwisting rates (20.3+/-8.7 degrees/s), while normally active individuals had increased untwisting rates (-16.2+/-32.1 degrees/s) in response to LBNP (P<0.05). Changes in peak untwisting rate were significantly correlated with change in peak torsion (R=-0.87, P<0.05), with the change in early filling rate and VO2max, but not with changes in end-diastolic or end-systolic volume (P>0.05). We conclude that increased untwisting rates in normally active subjects may mitigate the drop in early filling rate with LBNP and thus may be a compensatory mechanism for the reduction in stroke volume with volume unloading. The opposite response in athletes, who showed a decreased untwisting rate, may contribute to their larger reductions in LV end-diastolic and stroke volumes with volume unloading and their orthostatic intolerance.