Karla M. Daniels

Expression of the Irisin Precursor FNDC5 in Skeletal Muscle Correlates With Aerobic Exercise Performance in Patients With Heart Failure

Background—Exercise-induced increase in peroxisome proliferator-activated receptor-&ggr; coactivator-1&agr; (PGC-1&agr;) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (FNDC5) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and because PGC-1&agr; and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF. Methods and Results—Systolic HF (left ventricular ejection fraction ⩽40%) patients underwent cardiopulmonary exercise testing to evaluate aerobic performance. High versus low aerobic performance was assessed using oxygen consumption (peak VO2 [>14 versus ⩽14 mL O2·kg−1·min−1]) and ventilatory efficiency (VE/VCO2 slope [<34 versus ≥34]). Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression. Twenty-four patients were studied. FNDC5 (5.7±3.5 versus 3.1±1.2, P<0.05) and PGC-1&agr; (9.9±5.9 versus 4.5±1.9, P<0.01) gene expressions were greater in the high-peak VO2 group; correlation between FNDC5 and PGC-1&agr; was significant (r=0.56, P<0.05) only in the high-peak VO2 group. Similarly, FNDC5 and PGC-1&agr; gene expression was greater in the high-performance group based on lower VE/VCO2 slopes (5.8±3.6 versus 3.3±1.4, P<0.05 and 9.7±6 versus 5.3±3.4, P<0.05); FNDC5 also correlated with PGC-1&agr; (r=0.55, P<0.05) only in the low VE/VCO2 slope group. Conclusions—This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients.

Cardiac Rehabilitation for Women across the Lifespan

Cardiac rehabilitation improves function and compliance and also reduces morbidity and mortality in female and male cardiovascular disease patients but remains significantly underutilized. At every age, and especially in their senior years, female cardiovascular disease patients are under-referred relative to men. Lack of standardized referral processes, misconceptions by physicians and patients, and idiosyncrasies of female pathophysiology contribute to this pattern. Moreover, confounding factors of age, socioeconomic status, and sex-specific roles and responsibilities exacerbate the problem. This review summarizes barriers to cardiac rehabilitation for female cardiac patients, and highlights opportunities for increased participation and benefit.

Ranolazine in Symptomatic Diabetic Patients Without Obstructive Coronary Artery Disease: Impact on Microvascular and Diastolic Function

Background Treatments for patients with myocardial ischemia in the absence of angiographic obstructive coronary artery disease are limited. In these patients, particularly those with diabetes mellitus, diffuse coronary atherosclerosis and microvascular dysfunction is a common phenotype and may be accompanied by diastolic dysfunction. Our primary aim was to determine whether ranolazine would quantitatively improve exercise‐stimulated myocardial blood flow and cardiac function in symptomatic diabetic patients without obstructive coronary artery disease. Methods and Results We conducted a double‐blinded crossover trial with 1:1 random allocation to the order of ranolazine and placebo. At baseline and after each 4‐week treatment arm, left ventricular myocardial blood flow and coronary flow reserve (CFR; primary end point) were measured at rest and after supine bicycle exercise using 13N‐ammonia myocardial perfusion positron emission tomography. Resting echocardiography was also performed. Multilevel mixed‐effects linear regression was used to determine treatment effects. Thirty‐five patients met criteria for inclusion. Ranolazine did not significantly alter rest or postexercise left ventricular myocardial blood flow or CFR. However, patients with lower baseline CFR were more likely to experience improvement in CFR with ranolazine (r=−0.401, P=0.02) than with placebo (r=−0.188, P=0.28). In addition, ranolazine was associated with an improvement in E/septal e′ (P=0.001) and E/lateral e′ (P=0.01). Conclusions In symptomatic diabetic patients without obstructive coronary artery disease, ranolazine did not change exercise‐stimulated myocardial blood flow or CFR but did modestly improve diastolic function. Patients with more severe baseline impairment in CFR may derive more benefit from ranolazine. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01754259.

Dynamic assessment of ventilatory efficiency during recovery from peak exercise to enhance cardiopulmonary exercise testing

Background: While cardiopulmonary exercise testing (CPX) assessment is generally regarded as an optimal means to assess functional capacity in heart failure (HF) patients, strength parameters are omitted. CPX indices collected in recovery may provide additional insight regarding function, including strength. Design and methods: We performed a cross-sectional controlled study. Systolic HF patients (aged ≥50 years) and age-matched controls were assessed using CPX and strength evaluations. Standard CPX indices were assessed during exercise (peak oxygen consumption [VO2], first ventilatory threshold [1stVT], and ventilatory efficiency [VE/VCO2 slope]) as well as indices at 1-minute recovery (1 min VO2, 1 min VE/VCO2, and 1 min heart rate recovery [HRR]) and differences between peak and 1-minute recovery (ΔVO2 and ΔVE/VCO2). Lower extremity strength was evaluated using the 1-repetition maximum (1RM) and power. Results: Seventy adults (31 HF; 39 controls), mean age 66.2 ± 9.7 years were evaluated. Peak VO2 (15.4 ± 4.2 versus 23.4 ± 6.6 mlO2·kg−1·min−1, p < 0.0001) and 1stVT (10.9 ± 2.1 versus 14.4 ± 4.0mlO2·kg−1·min−1, p < 0.0001) were diminished in HF versus controls and VE/VCO2 slope was increased (42.3 ± 12.2 versus 35.4 ± 8.3, p < 0.01). HF patients had reduced 1minVO2 (13.1 ± 2.9 versus 16.3 ± 3.7 mlO2·kg−1·min−1, p < 0.0001), 1 min HRR (6.7 ± 11.4 versus 12.4 ± 7.6 beats, p < 0.02), and ΔVO2 (2.43 ± 2.3 versus 7.3 ± 5.0 mlO2·kg−1·min−1, p < 0.0001) as well as increased 1 min VE/VCO2 (37 ± 7.5 versus 31.5 ± 4.4, p < 0.001) and ΔVE/VCO2 (1.17 ± 3.0 versus −0.5 ± 1.3, p < 0.0001). Strength parameters were relatively lower in HF. While CPX exercise parameters correlated with strength, stronger correlations were observed between CPX recovery parameters and strength. Conclusions: CPX recovery indices corroborate disease-specific aerobic differences and distinguish differences in strength. Recovery ventilatory efficiency enhances CPX’s value as a comprehensive physical function tool.

Serum adiponectin in non-cachectic heart failure patients.

Karla M. Daniels , Alexandra Zavin , Kelly Allsup , Jacob Joseph , Ross Arena , Antonio A. Lazzari , P. Christian Schulze , Stewart H. Lecker , Jonathan Brown , Daniel E. Forman a,b,⁎ a Brigham and Women’s Hospital, United States b VA Boston Healthcare System, United States c University of New Mexico, United States d Boston University School of Medicine, United States e Columbia University Medical Center, United States f Beth Israel Deaconess Medical Center, United States g Harvard Medical School, United States

THE SIX MINUTE WALK DISTANCE AS AN INDICATOR OF FRAILTY AND FUNCTIONAL INCAPACITY IN ELDERLY HEART FAILURE PATIENTS

While cardiopulmonary exercise testing (CPX) is commonly used as the gold standard for functional evaluation in heart failure (HF) management, it may not reflect many pertinent aspects of physical function. We studied CPX and 6 minute walk distance (6MWD) in relation to strength and integrative

CORRELATIONS BETWEEN RECOVERY KINETICS AND SKELETAL MUSCLE GENE EXPRESSION IN SYSTOLIC HEART FAILURE

Results: 70 male patients were studied (31 HF and 39 controls). Both Δmin1VO2 (2.43±2.3 vs. 7.3±5 mlO2•kg-1•min-1; p<0.0001) and Δmin2VO2 (7.8±4 vs. 15.2±7.3 mlO2•kg-1•min-1; p<0.0001) were lower in HF. Genes induced in atrophying muscle negatively correlated with 2-minute recovery kinetics in controls, meanwhile this association was not observed in HF (Table). Genes suppressed in atrophying muscle correlated with recovery kinetics in HF but not controls. Conclusions: Recovery from exercise is associated with divergent programs of skeletal muscle adaptation in the healthy state compared to HF.

Ventilatory PowerClinical Perspective

Background—Minute ventilation/CO2 production (VE/VCO2) slope is an index determined by cardiopulmonary exercise testing, which incorporates pertinent cardiac, pulmonary, and skeletal muscle physiology into a substantive composite assessment. The VE/VCO2 slope has many applications, including utility as a well-validated prognostic gauge for patients with heart failure (HF). In this study, we combine VE/VCO2 slope with systolic blood pressure, creating a novel index that we labeled ventilatory power. Ventilatory power links the combined physiology inherent in the VE/VCO2 slope to peripheral pressure, adding an additional dimension pertinent to HF assessment. Whereas the related concept of circulatory power links peak oxygen consumption with peak systolic blood pressure as a prognostic index, we hypothesized that ventilatory power would provide greater prognostic discrimination than VE/Vco2 slope, peak oxygen consumption, and circulatory power for patients with systolic HF. Methods and Results—Patients with systolic HF (left ventricular ejection fraction ⩽35%) underwent symptom-limited cardiopulmonary exercise testing as part of routine management and were followed for up to 4 years for major cardiac events (mortality, left ventricular assist device implantation, and heart transplantation). Eight hundred seventy-five patients with HF (left ventricular ejection fraction, 26±9%; mean age, 55±14) were studied. Cardiopulmonary exercise testing indices peak oxygen consumption, VE/VCO2 slope, circulatory power, and ventilatory power were all predictive of cardiac events (P<0.001). Multivariate analysis demonstrated that ventilatory power was the strongest indicator of prognosis. Conclusions—Although circulatory power and traditional cardiopulmonary exercise testing parameters can be used to predict prognosis among patients with HF, ventilatory power provides relatively greater prognostic discrimination and may constitute a relatively more useful composite tool.Background— Minute ventilation/CO2 production (VE/Vco2) slope is an index determined by cardiopulmonary exercise testing, which incorporates pertinent cardiac, pulmonary, and skeletal muscle physiology into a substantive composite assessment. The VE/Vco2 slope has many applications, including utility as a well-validated prognostic gauge for patients with heart failure (HF). In this study, we combine VE/Vco2 slope with systolic blood pressure, creating a novel index that we labeled ventilatory power. Ventilatory power links the combined physiology inherent in the VE/Vco2 slope to peripheral pressure, adding an additional dimension pertinent to HF assessment. Whereas the related concept of circulatory power links peak oxygen consumption with peak systolic blood pressure as a prognostic index, we hypothesized that ventilatory power would provide greater prognostic discrimination than VE/Vco2 slope, peak oxygen consumption, and circulatory power for patients with systolic HF. Methods and Results— Patients with systolic HF (left ventricular ejection fraction ≤35%) underwent symptom-limited cardiopulmonary exercise testing as part of routine management and were followed for up to 4 years for major cardiac events (mortality, left ventricular assist device implantation, and heart transplantation). Eight hundred seventy-five patients with HF (left ventricular ejection fraction, 26±9%; mean age, 55±14) were studied. Cardiopulmonary exercise testing indices peak oxygen consumption, VE/Vco2 slope, circulatory power, and ventilatory power were all predictive of cardiac events ( P <0.001). Multivariate analysis demonstrated that ventilatory power was the strongest indicator of prognosis. Conclusions— Although circulatory power and traditional cardiopulmonary exercise testing parameters can be used to predict prognosis among patients with HF, ventilatory power provides relatively greater prognostic discrimination and may constitute a relatively more useful composite tool.

Ventilatory PowerClinical Perspective: A Novel Index That Enhances Prognostic Assessment of Patients With Heart Failure

Background—Minute ventilation/CO2 production (VE/VCO2) slope is an index determined by cardiopulmonary exercise testing, which incorporates pertinent cardiac, pulmonary, and skeletal muscle physiology into a substantive composite assessment. The VE/VCO2 slope has many applications, including utility as a well-validated prognostic gauge for patients with heart failure (HF). In this study, we combine VE/VCO2 slope with systolic blood pressure, creating a novel index that we labeled ventilatory power. Ventilatory power links the combined physiology inherent in the VE/VCO2 slope to peripheral pressure, adding an additional dimension pertinent to HF assessment. Whereas the related concept of circulatory power links peak oxygen consumption with peak systolic blood pressure as a prognostic index, we hypothesized that ventilatory power would provide greater prognostic discrimination than VE/Vco2 slope, peak oxygen consumption, and circulatory power for patients with systolic HF. Methods and Results—Patients with systolic HF (left ventricular ejection fraction ⩽35%) underwent symptom-limited cardiopulmonary exercise testing as part of routine management and were followed for up to 4 years for major cardiac events (mortality, left ventricular assist device implantation, and heart transplantation). Eight hundred seventy-five patients with HF (left ventricular ejection fraction, 26±9%; mean age, 55±14) were studied. Cardiopulmonary exercise testing indices peak oxygen consumption, VE/VCO2 slope, circulatory power, and ventilatory power were all predictive of cardiac events (P<0.001). Multivariate analysis demonstrated that ventilatory power was the strongest indicator of prognosis. Conclusions—Although circulatory power and traditional cardiopulmonary exercise testing parameters can be used to predict prognosis among patients with HF, ventilatory power provides relatively greater prognostic discrimination and may constitute a relatively more useful composite tool.Background— Minute ventilation/CO2 production (VE/Vco2) slope is an index determined by cardiopulmonary exercise testing, which incorporates pertinent cardiac, pulmonary, and skeletal muscle physiology into a substantive composite assessment. The VE/Vco2 slope has many applications, including utility as a well-validated prognostic gauge for patients with heart failure (HF). In this study, we combine VE/Vco2 slope with systolic blood pressure, creating a novel index that we labeled ventilatory power. Ventilatory power links the combined physiology inherent in the VE/Vco2 slope to peripheral pressure, adding an additional dimension pertinent to HF assessment. Whereas the related concept of circulatory power links peak oxygen consumption with peak systolic blood pressure as a prognostic index, we hypothesized that ventilatory power would provide greater prognostic discrimination than VE/Vco2 slope, peak oxygen consumption, and circulatory power for patients with systolic HF. Methods and Results— Patients with systolic HF (left ventricular ejection fraction ≤35%) underwent symptom-limited cardiopulmonary exercise testing as part of routine management and were followed for up to 4 years for major cardiac events (mortality, left ventricular assist device implantation, and heart transplantation). Eight hundred seventy-five patients with HF (left ventricular ejection fraction, 26±9%; mean age, 55±14) were studied. Cardiopulmonary exercise testing indices peak oxygen consumption, VE/Vco2 slope, circulatory power, and ventilatory power were all predictive of cardiac events ( P <0.001). Multivariate analysis demonstrated that ventilatory power was the strongest indicator of prognosis. Conclusions— Although circulatory power and traditional cardiopulmonary exercise testing parameters can be used to predict prognosis among patients with HF, ventilatory power provides relatively greater prognostic discrimination and may constitute a relatively more useful composite tool.