Michael F. La Fountaine

Age-related prevalence of low testosterone in men with spinal cord injury

Abstract Objective To describe the relationship of advancing age in persons with chronic spinal cord injury (SCI) on the prevalence of low testosterone in men with SCI compared to historical normative data from able-bodied men in the general population. Design Retrospective, cross-sectional study. Two hundred forty-three healthy, non-ambulatory outpatient men with chronic SCI from age of 21 to 78 years were included in this retrospective analysis. Results Forty-six percent of men with SCI were identified as having low serum total testosterone concentrations (total testosterone <11.3 nmol/l). The age-related decline in SCI for total serum testosterone concentration was 0.6%/year compared to 0.4%/year in the Massachusetts Male Aging Study. Between the third and eighth decade of life, men with SCI had a 15, 39, 50, 53, 58, and 57% prevalence rate of low serum total testosterone, which is higher than values reported for each decade of life for able-bodied men in the Baltimore Longitudinal Study on Aging. Conclusion Compared with the general population, low serum total testosterone concentration occurs earlier in life in men with SCI, at a higher prevalence by decade of life, and their age-related decline in circulating total testosterone concentration is greater. Studies of T replacement therapy in men with SCI should assist in determining the possible functional and clinical benefits from reversing low serum total testosterone concentration.

Transient suppression of heart rate complexity in concussed athletes

Heart rate variability (HRV) and complexity (HRC) were calculated at rest and during an isometric hand grip test (IHGT) within 48-hours (48 h) and two weeks (Week Two) of a concussion in athletes (CG) and control subjects. No differences were present at rest or in HRV during IGHT. HRC was significantly lower in the CG compared to controls at 48 h during IHGT. In CG at Week Two during IHGT, HRC was significantly greater than 48 h observations and not significantly different than controls. The findings suggest that HRC may have utility in detecting efferent cardiac autonomic anomalies within two weeks of concussion.

Increased QT Interval Variability in 3 Recently Concussed Athletes: An Exploratory Observation

CONTEXT The QT interval variability index (QTVI) is a noninvasive measure of beat-to-beat fluctuations of the QT interval as seen from a single electrocardiographic lead. It represents the relationship between the respective variabilities of the QT and R-R intervals. Recently, the QTVI was demonstrated to be an index of vagal cardiac autonomic modulation in resting conditions. OBJECTIVE To determine whether QTVI varied in athletes at 48 hours, 1 week, and 2 weeks after a concussive head injury. DESIGN Case series. SETTING Testing facility. PATIENTS OR OTHER PARTICIPANTS Three athletes with recent concussions and 3 uninjured athletes with similar demographic factors. MAIN OUTCOME MEASURE(S) Continuous 3-lead electrocardiograms were obtained in a seated, resting position over 2 successive weeks. Separate, unpaired t tests were performed to determine whether group-visit differences were present in the QTVI at 48 hours, 1 week, or 2 weeks. RESULTS No demographic differences were present between groups. At 48 hours, the QTVI was greater in the concussion group than in the matched controls. At weeks 1 and 2, the QTVI in the concussion group was lower than at 48 hours and not different from that of the control group. CONCLUSIONS Vagal cardiac autonomic modulation, as quantified by the QTVI, appeared to be negatively affected in concussed athletes within 48 hours of injury, resolved within 1 week, and remained at control group levels 2 weeks later. Serial assessments of QTVI may be of clinical utility in identifying suspected cases of acute concussion and may provide helpful information for determining when an athlete can return to play safely.

Autonomic Nervous System Responses to Concussion: Arterial Pulse Contour Analysis

The arterial pulse wave (APW) has a distinct morphology whose contours reflect dynamics in cardiac function and peripheral vascular tone as a result of sympathetic nervous system (SNS) control. With a transition from rest to increased metabolic demand, the expected augmentation of SNS outflow will not only affect arterial blood pressure and heart rate but it will also induce changes to the contours of the APW. Following a sports concussion, a transient state cardiovascular autonomic dysfunction is present. How this state affects the APW has yet to be described. A prospective, parallel-group study on cardiovascular autonomic control (i.e., digital electrocardiogram and continuous beat-to-beat blood pressure) was performed in the seated upright position in 10 athletes with concussion and 7 non-injured control athletes. Changes in APW were compared at rest and during the first 60 s (F60) of an isometric handgrip test (IHGT) in concussed athletes and non-injured controls within 48 h and 1 week of injury. The concussion group was further separated by the length of time until they were permitted to return to play (RTP > 1week; RTP ≤ 1week). SysSlope, an indirect measurement of stroke volume, was significantly lower in the concussion group at rest and during F60 at 48 h and 1week; a paradoxical decline in SysSlope occurred at each visit during the transition from rest to IHGT F60. The RTP > 1week group had lower SysSlope (405 ± 200; 420 ± 88; 454 ± 236 mmHg/s, respectively) at rest 48 h compared to the RTP ≤ 1week and controls. Similarly at 48 h rest, several measurements of arterial stiffness were abnormal in RTP > 1week compared to RTP ≤ 1week and controls: peak-to-notch latency (0.12 ± 0.04; 0.16 ± 0.02; 0.17 ± 0.05, respectively), notch relative amplitude (0.70 ± 0.03; 0.71 ± 0.04; 0.66 ± 0.14, respectively), and stiffness index (6.4 ± 0.2; 5.7 ± 0.4; 5.8 ± 0.5, respectively). Use of APW revealed that concussed athletes have a transient increase in peripheral artery stiffness, which may be a compensatory adaptation to a paradoxical decline of stroke volume during the transition from rest to a state of increased metabolic demand within 48 h of concussion. This dysfunction of the SNS appeared to be more pronounced among concussed athletes who were removed from participation for >1 week compared to those who resumed play within 7 days.

Lean tissue mass and energy expenditure are retained in hypogonadal men with spinal cord injury after discontinuation of testosterone replacement therapy

Abstract Objective To determine whether favorable changes to lean tissue mass (LTM), resting energy expenditure (REE), and testosterone (T) that occurred with 12 months of physiological testosterone replacement therapy (TRT) were retained 6 months after discontinuing treatment. Design Prospective, open-label, controlled drug intervention trial. Setting Metropolitan area hospitals. Subjects Eugonadal (n = 11) and hypogonadal (n = 13) men with chronic spinal cord injury (SCI). Interventions Hypogonadal subjects received a 5 or 10 mg transdermal T patch daily for 12 months, with adjustment of the dose to normalize the serum T concentration; TRT was discontinued after 12 months (TRT-12M) and subjects were followed for an additional 6 months and re-evaluated (Post-TRT). Total body dual energy X-ray absorptiometry and blood draws were performed at baseline (BL) prior to TRT, TRT-12M, and Post-TRT. Eugonadal subjects did not receive treatment and were evaluated at comparable time points. Results There were no significant differences between groups prior to TRT at BL for any of the study endpoints. In the hypogonadal group, a significant increase in LTM was observed from BL to TRT-12M (50.2 ± 7.4 vs. 52.9 ± 6.8 kg, P < 0.01), which persisted Post-TRT compared to BL (52.2 ± 7.8 kg, P < 0.05). The increase in REE from BL to TRT-12M (1283 ± 246 vs. 1410 ± 250 kcal/day) was also retained at Post-TRT (1393 ± 220 kcal/day). These sustained improvements in LTM and REE after termination of anabolic hormonal therapy may be associated with persistent beneficial effects on health and physical function of hypogonadal men with chronic SCI.

The QT Variability Index and Cardiac Autonomic Modulation: Perspectives from Apparently Healthy Men with Spinal Cord Injury

Objective: To describe the effect of spinal cord injury (SCI) on the QT variability index (QTVI). Methods: Digital electrocardiograms from 113 age-matched men (40 with tetraplegia, 26 with high paraplegia, 17 low paraplegia and 31 controls) were analyzed. RR interval, heart rate (HR) variability [total power (TPRR), low frequency (LFRR) and high frequency (HFRR)], QT interval duration, Bazett HR-corrected QT (QTc), QT interval variance (QTVN) and QTVI were compared. Results: Significant group main effects were present for RR, QTc, TPRR and LFRR, but not QT duration, QTVN or HFRR. Post hoc comparisons revealed the following: (1) longer RR in controls versus subjects with high paraplegia and low paraplegia, and in subjects with tetraplegia versus high paraplegia and low paraplegia; (2) QTc was longer in subjects with low paraplegia versus controls and shorter in subjects with tetraplegia versus high paraplegia, and (3) TPRR and LFRR were different in controls and subjects with high paraplegia compared to those with low paraplegia. QTVI was significantly elevated in all SCI groups compared to controls. Significant negative correlations between QTVI and HFRR were observed in all SCI groups, and TPRR and LFRR in subjects with tetraplegia and high paraplegia only. Age was negatively correlated in controls. Conclusions: QTVI is negatively affected in otherwise healthy SCI men compared to age-matched controls. This observation appears to reflect the attenuation of vagal modulation, sympathetic impairment above the sixth thoracic vertebra and/or a heightened degree of cardiovascular disease risk.

The influence of cardiac autonomic activity on the QT-variability index in able-bodied and incomplete spinal cord injured individuals

OBJECTIVES To investigate, via autonomic blockade, if the QT-variability index (QTVI) is a measure of cardiac autonomic regulation in able-bodied (AB) and incomplete spinal cord injured (SCI) individuals. METHODS Four SCI (41.6±13.4years; C4-C7, AIS B-D, 13.4±13.4years post injury) and 4 AB (33.0±7.8years) individuals were tested. QTVI was determined from electrocardiographic readings obtained during supine rest and cardiovascular (CV) stress, with and without autonomic blockade. CV stress was induced by 40° head-up tilt, the hand submerged in 10°C water and the jaw clenched. Autonomic blockade was achieved with metoprolol (β-blockade) and atropine (cholinergic blockade). RESULTS There was no group×condition interaction for QTVI, although there was a significant main effect for condition. After collapsing across groups, QTVI increased with CV stress (p=0.01) and decreased with subsequent β-blockade (p=0.04), suggesting that during CV stress, QTVI is reflective of cardiac sympathetic activity. During supine rest, β-blockade did not change QTVI (p=0.24), however, cholinergic blockade increased QTVI (p<0.001), suggesting that during rest, QTVI is inversely related to cardiac parasympathetic regulation. CONCLUSION During times of CV stress, QTVI reflects cardiac sympathetic activity, while during resting conditions, QTVI is inversely related to cardiac parasympathetic activity. These relationships persist after autonomically incomplete SCI.

Low-dose baclofen therapy raised plasma insulin-like growth factor-1 concentrations, but not into the normal range in a predictable and sustained manner in men with chronic spinal cord injury

Abstract Objective To evaluate, whether once-daily oral baclofen administration increases and/or sustains plasma insulin-like growth factor-1 (IGF-1) concentration in 11 men with chronic spinal cord injury (SCI) and IGF-1 deficiency (i.e. <250 ng/ml). Design Prospective, open-label, dose titration study. Baclofen was administered at 20 mg/day for 8 weeks; then increased to 40 mg/day for another 8 weeks. Plasma IGF-1 and self-reported side effects were measured at baseline and every other week for the duration of the study. Results The subjects were 43 ± 12 years old, had duration of injury of 20 ± 12 years; eight subjects had a complete motor injury, and eight had paraplegia. Nine of 11 subjects completed the 20 mg/day treatment and 5 subjects completed the 40 mg/day treatment. Plasma IGF-1 levels improved with each baclofen dose; however, only one subject increased from baseline and remained above the targeted physiological range of 250 ng/ml throughout treatment. A significant increase in IGF-1concentration was observed between baseline and week 2 (154 ± 63 vs. 217 ± 69 ng/ml; P < 0.05), weeks 8 and 10 (188 ± 95 vs. 228 ± 93 ng/ml; P < 0.05), and weeks 8 and 16 (188 ± 95 vs. 259 ± 92 ng/ml; P < 0.05). No serious side effects were observed at 20 mg/day; the 40 mg/day dose was less well tolerated. Conclusion Baclofen was not effective at sustaining plasma IGF-1 concentrations in the physiological range in men with chronic SCI.

Effect of functional sympathetic nervous system impairment of the liver and abdominal visceral adipose tissue on circulating triglyceride-rich lipoproteins

Background Interruption of sympathetic innervation to the liver and visceral adipose tissue (VAT) in animal models has been reported to reduce VAT lipolysis and hepatic secretion of very low density lipoprotein (VLDL) and concentrations of triglyceride-rich lipoprotein particles. Whether functional impairment of sympathetic nervous system (SNS) innervation to tissues of the abdominal cavity reduce circulating concentrations of triglyceride (TG) and VLDL particles (VLDL-P) was tested in men with spinal cord injury (SCI). Methods One hundred-three non-ambulatory men with SCI [55 subjects with neurologic injury at or proximal to the 4th thoracic vertebrae (↑T4); 48 subjects with SCI at or distal to the 5th thoracic vertebrae (↓T5)] and 53 able-bodied (AB) subjects were studied. Fasting blood samples were obtained for determination of TG, VLDL-P concentration by NMR spectroscopy, serum glucose by autoanalyzer, and plasma insulin by radioimmunoassay. VAT volume was determined by dual energy x-ray absorptiometry imaging with calculation by a validated proprietary software package. Results Significant group main effects for TG and VLDL-P were present; post-hoc tests revealed that serum TG concentrations were significantly higher in ↓T5 group compared to AB and ↑T4 groups [150±9 vs. 101±8 (p<0.01) and 112±8 mg/dl (p<0.05), respectively]. VLDL-P concentration was significantly elevated in ↓T5 group compared to AB and ↑T4 groups [74±4 vs. 58±4 (p<0.05) and 55±4 μmol/l (p<0.05)]. VAT volume was significantly higher in both SCI groups than in the AB group, and HOMA-IR was higher and approached significance in the SCI groups compared to the AB group. A linear relationship between triglyceride rich lipoproteins (i.e., TG or Large VLDL-P) and VAT volume or HOMA-IR was significant only in the ↓T5 group. Conclusions Despite a similar VAT volume and insulin resistance in both SCI groups, the ↓T5 group had significantly higher serum TG and VLDL-P values than that observed in the ↑T4 and the AB control groups. Thus, level of injury is an important determinate of the concentration of circulating triglyceride rich lipoproteins, which may play a role in the genesis of cardiometabolic dysfunction.

Testosterone replacement therapy improves QTaVI in hypogonadal men with spinal cord injury.

Aim: To determine the effect of a 12-month intent-to-treat testosterone (T) replacement therapy (TRT) trial on QTa interval variability (QTaVI) in hypogonadal (HG) men with spinal cord injury (SCI). Method: A prospective, controlled 12-month TRT trial was completed in 22 healthy, chronic, nonambulatory men with SCI. Based on serum T concentration, subjects were designated as HG (≤11.3 nmol/l) or eugonadal (EG ≥11.4 nmol/l). Digital 3-lead electrocardiograms were performed. Heart rate (RR), heart rate variability [including total power (TPRR), low frequency (LFRR) and high frequency (HFRR)], QTa, QTe, and RT intervals, QTC (Bazett formula), QTVN, and QTaVI were calculated and evaluated at baseline and at 12 months. Lipoprotein profiles (triglycerides, total cholesterol, low-density and high-density lipoproteins) were obtained at the respective time points. Results: Based on serum T concentration, 13 subjects were designated as HG and 11 as EG. During the trial, there were no group differences for RR, QTa, QTe or RT intervals, QTC, TPRR, HFRR, or lipoproteins. The HG group was older (p < 0.05) and their LFRR was lower (p < 0.05) at baseline. At baseline, QTaVI was significantly greater in the HG group compared to the EG group [-0.17 (0.92) vs. -1.07 (0.90); p < 0.05]. After TRT, this group difference was no longer present [-0.44 (0.87) vs. -0.65 (0.85)] and the change in the HG group was significant (p < 0.05). Conclusion: Hypogonadism in men with SCI was associated with elevated QTaVI at baseline. After 12 months of physiological TRT, the QTaVI improved in association with raising T into the normal range. These findings occurred independently of the prolongation of the QT interval.