Ferdinando Iellamo

Effect of Long-Acting Testosterone Treatment on Functional Exercise Capacity, Skeletal Muscle Performance, Insulin Resistance, and Baroreflex Sensitivity in Elderly Patients With Chronic Heart Failure. A Double-Blind, Placebo-Controlled, Randomized Study

OBJECTIVES This study investigated the effect of a 12-week long-acting testosterone administration on maximal exercise capacity, ventilatory efficiency, muscle strength, insulin resistance, and baroreflex sensitivity (BRS) in elderly patients with chronic heart failure (CHF). BACKGROUND CHF is characterized by a metabolic shift favoring catabolism and impairment in skeletal muscle bulk and function that could be involved in the pathophysiology of heart failure. METHODS Seventy elderly patients with stable CHF-median age 70 years, ejection fraction 31.8 +/- 7%-were randomly assigned to receive testosterone (n = 35, intramuscular injection every 6 weeks) or placebo (n = 35), both on top of optimal medical therapy. At baseline and at the end of the study, all patients underwent echocardiogram, cardiopulmonary exercise test, 6-min walk test (6MWT), quadriceps maximal voluntary contraction (MVC), and isokinetic strength (peak torque) and BRS assessment (sequences technique). RESULTS Baseline peak oxygen consumption (VO(2)) and quadriceps isometric strength showed a direct relation with serum testosterone concentration. Peak VO(2) significantly improved in testosterone but was unchanged in placebo. Insulin sensitivity was significantly improved in testosterone. The MVC and peak torque significantly increased in testosterone but not in placebo. The BRS significantly improved in testosterone but not in placebo. Increase in testosterone levels was significantly related to improvement in peak VO(2) and MVC. There were no significant changes in left ventricular function either in testosterone or placebo. CONCLUSIONS These results suggest that long-acting testosterone therapy improves exercise capacity, muscle strength, glucose metabolism, and BRS in men with moderately severe CHF. Testosterone benefits seem to be mediated by metabolic and peripheral effects.

Heart rate variability explored in the frequency domain: a tool to investigate the link between heart and behavior.

The neural regulation of circulatory function is mainly effected through the interplay of the sympathetic and vagal outflows. This interaction can be explored by assessing cardiovascular rhythmicity with appropriate spectral methodologies. Spectral analysis of cardiovascular signal variability, and in particular of RR period (heart rate variability, HRV), is a widely used procedure to investigate autonomic cardiovascular control and/or target function impairment. The oscillatory pattern which characterizes the spectral profile of heart rate and arterial pressure short-term variability consists of two major components, at low (LF, 0.04-0.15Hz) and high (HF, synchronous with respiratory rate) frequency, respectively, related to vasomotor and respiratory activity. With this procedure the state of sympathovagal balance modulating sinus node pacemaker activity can be quantified in a variety of physiological and pathophysiological conditions. Changes in sympathovagal balance can be often detected in basal conditions, however a reduced responsiveness to an excitatory stimulus is the most common feature that characterizes numerous pathophysiological states. Moreover the attenuation of an oscillatory pattern or its impaired responsiveness to a given stimulus can also reflect an altered target function and thus can furnish interesting prognostic markers. The dynamic assessment of these autonomic changes may provide crucial diagnostic, therapeutic and prognostic information, not only in relation to cardiovascular, but also non-cardiovascular disease. As linear methodologies fail to provide significant information in conditions of extremely reduced variability (e.g. strenuous exercise, heart failure) and in presence of rapid and transients changes or coactivation of the two branches of autonomic nervous system, the development of new non-linear approaches seems to provide a new perspective in investigating neural control of cardiovascular system.

Conversion From Vagal to Sympathetic Predominance With Strenuous Training in High-Performance World Class Athletes

Background—Benefits of moderate endurance training include increases in parasympathetic activity and baroreflex sensitivity (BRS) and a relative decrease in sympathetic tone. However, the effect of very intensive training load on neural cardiovascular regulation is not known. We tested the hypothesis that strenuous endurance training, like in high-performance athletes, would enhance sympathetic activation and reduce vagal inhibition. Methods and Results—We studied the entire Italian junior national team of rowing (n=7) at increasing training loads up to 75% and 100% of maximum, the latter ∼20 days before the Rowing World Championship. Autoregressive power spectral analysis was used to investigate RR interval and blood pressure (BP) variabilities. BRS was assessed by the sequences method. Increasing training load up to 75% of maximum was associated with a progressive resting bradycardia and increased indexes of cardiac vagal modulation and BRS. However, at 100% training load these effects were reversed, with increases in resting heart rate, diastolic BP, low-frequency RR interval, and BP variabilities and decreases in high-frequency RR variability and BRS. Three athletes later won medals in the World Championship. Conclusions—This study indicates that very intensive endurance training shifted the cardiovascular autonomic modulation from a parasympathetic toward a sympathetic predominance. This finding should be interpreted within the context of the substantial role played by the sympathetic nervous system in increasing cardiovascular performance at peak training. Whether the altered BP and autonomic function shown in this study might be in time hazardous to human cardiovascular system remains to be established.

Effects of a residential exercise training on baroreflex sensitivity and heart rate variability in patients with coronary artery disease : A randomized, controlled study

Background—Myocardial ischemia and infarction impair baroreflex sensitivity (BRS), which when depressed is predictive of future cardiac events after myocardial infarction (MI). The main objective of this study was to determine whether exercise training improves BRS in patients with coronary artery disease. Methods and Results—Ninety-seven male patients with and without a previous MI were recruited after myocardial revascularization surgery and randomized into trained (TR) or untrained (UTR) groups. TR patients underwent a residential exercise program at 85% of maximum heart rate (HRmax) consisting of 2 daily sessions 6 times a week for 2 weeks. Eighty-six patients (45 TR and 41 UTR) completed the study. BRS was assessed at baseline and at the end of the protocol by the spontaneous baroreflex method. The standard deviation of mean R-R interval (RRSD) was also assessed as a measure of heart rate variability. At baseline, there were no significant differences between TR and UTR patients in any variable. In TR patients, BRS increased from 3.0±0.3 to 5.3±0.7 ms/mm Hg (P <0.001), RRSD from 18.7±1.4 to 23.6±1.6 ms (P <0.01), and R-R interval from 792.0±15.5 to 851.3±20.5 ms (P <0.001). No significant changes occurred in UTR patients. Increases in BRS and RRSD were significant in patients either with or without a previous MI. Conclusions—Exercise training increases BRS and heart rate variability in patients with coronary artery disease. Improved cardiac autonomic function might add to the other benefits of exercise training in secondary prevention of ischemic heart disease.

Muscle metaboreflex contribution to sinus node regulation during static exercise: insights from spectral analysis of heart rate variability.

BACKGROUND It is currently assumed that during static exercise, central command increases heart rate (HR) through a decrease in parasympathetic activity, whereas the muscle metaboreflex raises blood pressure (BP) only through an increase in sympathetic outflow to blood vessels, because when the metaboreflex activation is maintained during postexercise muscle ischemia, BP remains elevated while HR recovers. We tested the hypotheses that the muscle metaboreflex contributes to HR regulation during static exercise via sympathetic activation and that the arterial baroreflex is involved in the HR recovery of postexercise muscle ischemia. METHODS AND RESULTS Eleven healthy male volunteers performed 4-minute static leg extension (SLE) at 30% of maximal voluntary contraction, followed by 4-minute arrested leg circulation (ALC). Autonomic regulation of HR was investigated by spectral analysis of HR variability (HRV), and baroreflex control of heart period was assessed by the spontaneous baroreflex method. SLE resulted in a significant increase in the low-frequency component of HRV that remained elevated during ALC. The normalized high-frequency component of HRV was reduced during SLE and returned to control levels during ALC. Baroreflex sensitivity was significantly reduced during SLE and returned to control levels during ALC when BP was kept elevated above the resting level while HR recovered. CONCLUSIONS The muscle metaboreflex contributes to HR regulation during static exercise via a sympathetic activation. The bradycardia that occurs during postexercise muscle ischemia despite the maintained sympathetic stimulus may be explained by a baroreflex-mediated increase in parasympathetic outflow to the sinoatrial node that overpowers the metaboreflex-induced cardiac sympathetic activation.

Testosterone therapy in women with chronic heart failure: A pilot double-blind, randomized, placebo-controlled study

OBJECTIVES The primary objective of this study was to assess the effect of a 6-month testosterone supplementation therapy on functional capacity and insulin resistance in female patients with chronic heart failure (CHF). BACKGROUND Patients with CHF show decreased exercise capacity and insulin sensitivity. Testosterone supplementation improves these variables in men with CHF. No study has evaluated the effects of testosterone supplementation on female patients with CHF. METHODS Thirty-six elderly female patients with stable CHF, (ejection fraction 32.9 ± 6) were randomly assigned (2:1 ratio) to receive testosterone transdermal patch (T group, n = 24) or placebo (P group, n = 12), both on top of optimal medical therapy. At baseline and after 6 months, patients underwent 6-min walking test (6MWT), cardiopulmonary exercise test, echocardiogram, quadriceps maximal isometric voluntary contraction, dynamic quadriceps isokinetic strength (peak torque), and insulin resistance assessment by homeostasis model. RESULTS Distance walked at 6MWT as well as peak oxygen consumption significantly improved in the T group, whereas they were unchanged in the P group (p < 0.05 for all comparisons). The homeostasis model was significantly reduced in the T group in comparison with the P group (-16.5% vs. +5%, respectively; p < 0.05). Maximal voluntary contraction and peak torque increased significantly in the T group but did not change in the P group. Increase in distance walked at 6MWT was related to the increase in free testosterone levels (r = 0.593, p = 0.01). No significant changes in echocardiographic parameters were observed in either group. No side effects requiring discontinuation of T were detected. CONCLUSIONS Testosterone supplementation improves functional capacity, insulin resistance, and muscle strength in women with advanced CHF. Testosterone seems to be an effective and safe therapy for elderly women with CHF.

Neural mechanisms of cardiovascular regulation during exercise

This brief review addresses current hypotheses concerning the reflex control of circulation during exercise in humans. In particular, the specific objective of this review is to describe how time and frequency domain analysis of blood pressure and heart rate variability signals permitted to gain new insights onto reflex mechanisms of cardiovascular regulation during exercise, without the need of perturbing the cardiovascular system from the outside, utilizing fully noninvasive approaches and avoiding artificially isolating the influence of the different neural pathways involved in the control of the cardiovascular system. Throughout the article, particular emphasis is given to the complexity and plasticity of the neural control of the circulation during exercise, by presenting data that show how the reflex mechanisms involved in cardiovascular regulation, namely, the arterial baroreflex and the muscle metaboreflex, may be differently modulated in relation to the muscular activity being performed, such as the type of exercise, the intensity of exercise and the size of active muscle masses.

Dose-response relationship of autonomic nervous system responses to individualized training impulse in marathon runners.

In athletes, exercise training induces autonomic nervous system (ANS) adaptations that could be used to monitor training status. However, the relationship between training and ANS in athletes has been investigated without regard for individual training loads. We tested the hypothesis that in long-distance athletes, changes in ANS parameters are dose-response related to individual volume/intensity training load and could predict athletic performance. A spectral analysis of heart rate (HR), systolic arterial pressure variability, and baroreflex sensitivity by the sequences technique was investigated in eight recreational athletes during a 6-mo training period culminating with a marathon. Individualized training load responses were monitored by a modified training impulse (TRIMP(i)) method, which was determined in each athlete using the individual HR and lactate profiling determined during a treadmill test. Monthly TRIMP(i) steadily increased during the training period. All the ANS parameters were significantly and very highly correlated to the dose of exercise with a second-order regression model (r(2) ranged from 0.90 to 0.99; P < 0.001). Variance, high-frequency oscillations of HR variability (HRV), and baroreflex sensitivity resembled a bell-shaped curve with a minimum at the highest TRIMP(i), whereas low-frequency oscillations of HR and systolic arterial pressure variability and the low frequency (LF)-to-high frequency ratio resembled an U-shaped curve with a maximum at the highest TRIMP(i). The LF component of HRV assessed at the last recording session was significantly and inversely correlated to the time needed to complete the nearing marathon. These results suggest that in recreational athletes, ANS adaptations to exercise training are dose related on an individual basis, showing a progressive shift toward a sympathetic predominance, and that LF oscillations in HRV at peak training load could predict athletic achievement in this athlete population.

Matched dose interval and continuous exercise training induce similar cardiorespiratory and metabolic adaptations in patients with heart failure

BACKGROUND The best format of exercise training in patients with chronic heart failure (CHF) is controversial. We tested the hypothesis that aerobic continuous training (ACT) and aerobic interval training (AIT) induce similar effects on functional capacity, central hemodynamics and metabolic profile in patients with postinfarction CHF provided that the training load is equated by an individually-tailored volume/intensity dose of exercise. METHODS Twenty patients with postinfarction CHF under optimal medical treatment were randomized to ACT or AIT for 12 weeks. Exercise training consisted in individualized loads prescribed according to the Training Impulses (TRIMPi) method, which was determined using the individual HR and lactate profiling obtained during a treadmill test at baseline. RESULTS Peak VO2 increased significantly by 22% with both ACT and AIT, without differences between the two training programs. Changes in anaerobic threshold and VE/VCO2 slope were not significantly different between ACT and AIT. Resting HR significantly decreased with both exercise modes. Resting cardiac output and stroke volume, left ventricular diastolic dimension and ejection fraction did not change from baseline with both exercise modes. Lipid profile and glucose metabolism were not substantially altered by ACT and AIT. CONCLUSIONS ACT and AIT both induce significant improvement in aerobic capacity in patients with postinfarction CHF, without significant differences between the two training modes, provided that patients are trained at the same, individually tailored, dose of exercise. The TRIMPi method might represent a step forward in the individualization of an aerobic training tailored to the patients clinical and functional status within cardiac rehabilitation programs.

Positive and Negative Feedback Mechanisms in the Neural Regulation of Cardiovascular Function in Healthy and Spinal Cord–Injured Humans

Background — We tested the hypothesis that in humans, hypertension/tachycardia and hypotension/bradycardia nonbaroreflex sequences that occur within spontaneous arterial pressure (AP) and R-R interval fluctuations are an expression of positive feedback mechanisms neurally regulating the cardiovascular system. Methods and Results — We studied 15 spinal cord–injured (SCI) subjects (8 tetraplegics and 7 paraplegics) and 8 healthy subjects. The occurrence of nonbaroreflex (NBseq) and baroreflex (Bseq) sequences, ie, hypertension-bradycardia and hypotension-tachycardia sequences, was assessed during rest and head-up tilt (HUT). The ratio between Bseq and NBseq (B/NB ratio) was also calculated. In resting conditions, the occurrence of NBseq was significantly lower (P <0.05) in tetraplegics (7.9±1.5) than in paraplegics (16.2±3.2) and normal subjects (19.0±3.5), whereas the occurrence of Bseq was not significantly different between the 3 groups (38.6±11.9 versus 45.4±6.0 versus 47.0±11.9). In tetraplegics, the B/NB ratio showed a marked, significant decrease (from 8.4±4.2 to 1.9±0.8, P <0.05) in response to HUT, whereas in normal subjects, it showed a significant increase (from 3.5±0.7 to 9.4±2.7, P <0.05). In paraplegics, the B/NB ratio did not change significantly in response to HUT (from 4.5±1.6 to 4.8±1.1). Conclusions — Our data suggest that nonbaroreflex sequences occur in humans and might represent the expression of an integrated, neurally mediated, feed-forward type of short-term cardiovascular regulation that is able to interact dynamically with feedback mechanisms of baroreflex origin.