Aldosterone and testosterone: two steroid hormones structurally related but with opposite electrophysiological properties during myocardial ischemia–reperfusion

Steroid hormones appear to be a key factor in the gender differences in the rates and severity of cardiovascular diseases. Aldosterone and testosterone have typical steroid ring structure, but despite this, they demonstrate very different properties. During acute myocardial ischemia–reperfusion, the deleterious impact of aldosterone is now well established. Conversely, the electrophysiological impact of testosterone in this context remained unknown. We used female rabbit in vitro models and standard microelectrode technique including right ventricle mimicking the ‘border zone’ existing between normal and ischemic/reperfused areas and isolated right ventricle experiments to assess the acute electrophysiological impact of both aldosterone and testosterone. During ischemia–reperfusion, acute superfusion of 10 and 100 nmol/L testosterone decreased normoxic and reperfused action potential duration at 90% (APD₉₀), systematically induced conduction blocks, and decreased APD₉₀ dispersion between ischemic and nonischemic areas (from 98 ± 4 to 57 ± 7 ms and 66 ± 3 ms, for, respectively, testosterone 10 and 100 nmol/L, P < 0.05). Testosterone 10 and 100 nmol/L concomitantly decreased sustained premature ventricular contraction (PVC) occurrence (from 55 to 0%, P < 0.05). Conversely, aldosterone 10 and 100 nmol/L increased normoxic and reperfused APD₉₀, APD₉₀ dispersion, and reperfusion‐induced PVCs. Furthermore, testosterone demonstrated cycle length‐dependent effects on APD₉₀ for high heart rate, whereas aldosterone did not exhibit any significant effect compared with controls. During acute myocardial ischemia–reperfusion, acute superfusion of physiological concentrations of testosterone seemed to be anti‐arrhythmic by removing a pro‐arrhythmic substrate (APD₉₀ dispersion), inducing conduction blocks and decreasing triggered activities (PVC occurrence). Further experiments are warranted to confirm our results.     

Distributed corpus callosum involvement in amyotrophic lateral sclerosis: a deterministic tractography study using q-ball imaging

Diffusion tensor imaging (DTI) has become a useful tool for investigating early white matter (WM) abnormalities in motor neuron disease. Furthermore, fiber tracking packages that apply multi-tensorial algorithms, such as q-ball imaging (QBI), have been proposed as alternative approaches to overcome DTI limitations in depicting fiber tracts with different orientations within the same voxel. We explored motor and extra-motor WM tract abnormalities in phenotypically heterogeneous amyotrophic lateral sclerosis (ALS) cases aiming to establish a consistent QBI-based WM signature of disease. We performed a whole-brain, QBI tract-based spatial statistics analysis with deterministic tractography of genu, body and splenium of corpus callosum (CC) and corticospinal tracts (CST) in 20 ALS patients (12 classical and 8 lower motor neuron variants) compared to 20 healthy controls. Mean tract length, fiber volume and density, and generalized fractional anisotropy were extracted and related to clinical indices of pyramidal impairment (upper motor neuron score), disease disability (ALS functional rating scale-revised) and progression. ALS patients showed significantly decreased fiber density and volume, and increased tract length in all regions of CC and left CST (p < 0.05, corrected). In CC body, pyramidal impairment was inversely correlated to fiber density (p = 0.01), while in CC splenium, clinical disability (p = 0.01) and progression (p = 0.02) were inversely correlated to tract length. Our findings further suggest that QBI tractography might represent a promising approach for investigating structural alterations in neurodegenerative diseases and confirm that callosal involvement is a consistent feature of most ALS variants, significantly related to both pyramidal dysfunction and disease disability.     

Heart rate and blood pressure variability in subjects with vasovagal syncope

Autonomic nervous system control in subjects with vasovagal syncope is controversial. In the present study, we used short-term spectral analysis to evaluate autonomic control in subjects with recurrent vasovagal syncope. We assessed the ability of spectral indices of HR (heart rate) variability to predict tilt-test responses. A series of 47 outpatients with recurrent vasovagal syncope and with positive responses to head-up tilt testing underwent a further study of RR variability during controlled breathing at rest and during tilt testing. During controlled breathing, RR interval variability of total power (TP(RR); P<0.001), low-frequency power (LF(RR); P<0.05), high-frequency power (HF(RR); P<0.001) and HF expressed in normalized units (HFnu(RR); P<0.001) were all higher, and LF expressed in normalized units (LFnu(RR)) and LF/HF ratio were lower in subjects with vasovagal syncope than in controls (P<0.001). To assess the ability of spectral components of RR variability to predict tilt-test responses, we prospectively studied 109 subjects with recurrent vasovagal syncope. The two normalized measures, HFnu(RR) and LFnu(RR), determined during controlled breathing alone predicted a positive tilt-test response (sensitivity, 76%; specificity, 99%; positive predictive value, 96%; and negative predictive value, 90%). During tilting, subjects with vasovagal syncope had lower SBP (systolic blood pressure; P<0.05), LF component of peak SBP variability (LF(SBP)) and LFnu(RR) than controls, and higher TP(RR), HF(RR), HFnu(RR) and alpha HF (P<0.001). These spectral data indicate that vagal sinus modulation is increased at rest in subjects with vasovagal syncope. Spectral analysis of RR variability during controlled breathing, a procedure that predicts tilt-test responses, could be a useful guide in choosing the method of tilt testing.     

CD4(+)CD25(+) regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness

CD4(+)CD25(+) regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4(+)CD25(-) T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact-dependent and cytokine independent. The role of TGF-beta1 in CD4(+)CD25(+) suppressor function remains unclear. While most studies have failed to reverse suppression with anti-transforming growth factor (TGF)-beta1 in vitro, one recent study has reported that CD4(+)CD25(+) T cells express cell surface TGF-beta1 and that suppression can be completely abrogated by high concentrations of anti-TGF-beta suggesting that cell-associated TGF-beta1 was the primary effector of CD4(+)CD25(+)-mediated suppression. Here, we have reevaluated the role of TGF-beta1 in CD4(+)CD25(+)-mediated suppression. Neutralization of TGF-beta1 with either monoclonal antibody (mAb) or soluble TGF-betaRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4(+)CD25(+) T cells. Responder T cells from Smad3(-/-) or dominant-negative TGF-beta type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-beta1-induced growth arrest, were as susceptible to CD4(+)CD25(+)-mediated suppression as T cells from wild-type mice. Furthermore, CD4(+)CD25(+) T cells from neonatal TGF-beta1(-/-) mice were as suppressive as CD4(+)CD25(+) from TGF-beta1(+/+) mice. Collectively, these results demonstrate that CD4(+)CD25(+) suppressor function can occur independently of TGF-beta1.     

Factors influencing heart rate variability power spectral analysis during controlled breathing in patients with chronic heart failure or hypertension and in healthy normotensive subjects

A decreased LFP (low-frequency power) spectral component of HRV [HR (heart rate) variability] is a risk factor for sudden death in patients with CHF (chronic heart failure). In the present study, we evaluated factors (age, arterial pressures and HR) influencing LFP and HFP (high-frequency power) components in short-term recordings during controlled breathing in patients with CHF or hypertension, and healthy normotensive subjects. In patients with CHF, we also compared LFP values with known markers of sudden death [NYHA (New York Heart Association) class, HR and ejection fraction]. All HRV measures were significantly lower in patients with CHF than in hypertensive and normotensive subjects (P<0.001), and in hypertensive than in normotensive subjects (P<0.05). Stepwise multiple regression analysis showed that, in patients with CHF, LFP was inversely associated with NYHA class (beta=-0.5, P<0.0001) and HR (beta=-0.2, P=0.001) and was positively associated with ejection fraction (beta=0.28, P<0.0001). In patients with CHF, LFP remained unchanged with age. In normotensive and hypertensive subjects, HFP decreased with age, but in patients with CHF it did not. In the >/=60<70 and >/=70 years of age subgroups, we found no difference between HFP in the three groups studied. Hence, in normotensives and hypertensives, LFP tended to diminish with age (beta=-0.4, P<0.0001 in normotensives; beta=-0.4, P<0.001 in hypertensives) and was inversely associated with HR (beta=-0.2, P=0.002 in normotensives; beta=-0.3, P=0.002 in hypertensives). Conversely, in patients with CHF, LFP is predominantly influenced by NYHA class, HR and ejection fraction, but not by age. LFP might therefore increase the sensitivity of factors already used in stratifying the risk of sudden death in patients with CHF.     

Patient perspective survey of total hip vs total knee arthroplasty surgery

A 42-item survey was developed and administered to determine patient perception of and satisfaction with total hip arthroplasty (THA) vs total knee arthroplasty (TKA). A total of 153 patients who had both primary THA and TKA for osteoarthritis with 1-year follow-up were identified. Survey response rate was 72%. Patients were more satisfied with THA meeting expectations for improvement in function and quality of life (P < .05), whereas pain relief expectations were equivalent. Most patients (70.9%) reported that TKA required more physiotherapy. One-year Oxford score and improvement in Oxford score from preoperative to 1 year were superior for THAs (P = .000). Despite equivalent pain relief, THAs trend toward higher satisfaction compared with TKAs. THA is more likely to "feel normal" with greater improvement in Oxford score. Recovery from TKA requires more physiotherapy and a longer time to achieve a satisfactory recovery status. Patients should be counseled accordingly.     

Effects of sildenafil citrate (viagra) on cardiac repolarization and on autonomic control in subjects with chronic heart failure

Background Cases of sudden death associated with sildenafil citrate use have been reported in men with coronary artery disease. The aim of this study was to investigate the drug's effect on cardiac repolarization and sinus autonomic and vascular control in men with mild chronic heart failure (CHF; New York Heart Association classification II). Changes in these variables could predispose patients to malignant ventricular arrhythmias. Method We measured QT dispersion, the QT-RR slope, and the index of QT variability (QTVI) and analyzed spectral power of RR and systolic blood pressure variability in 10 men with dilated cardiomyopathy and in 10 control subjects after administration of a single 50-mg oral dose of sildenafil citrate or placebo at rest (not followed with any attempt at intercourse). Results In both groups, oral sildenafil citrate decreased the systolic blood pressure (P <.05) and increased the heart rate (P <.05). In subjects with CHF, it also increased the QT-RR (P <.001) and QTVI (from −0.45 ± 0.07 to −0.27 ± 0.07; P <.001), but in controls, it increased the QTVI (from −1.20 ± 0.08 to −0.78 ± .014; P < .001). In these subjects and controls, oral sildenafil citrate induced a significant reduction in high frequency, expressed in absolute power (subjects with CHF: from 4.04 ± 0.14 to 3.43 ± 0.16 natural logarithm ms²; P <.001; controls: from 5.61 ± 0.44 to 4.98 ± 0.32 natural logarithm ms²; P <.05) and in normalized units (P <.05). In subjects with CHF but not in controls, it also significantly increased the low frequency to high frequency ratio (from 1.3 ± 0.12 to 1.89 ± 0.16; P <.001) and low frequency expressed in normalized units (P <.05).Sildenafil citrate caused no significant changes in the QT interval or dispersion. Conclusion These findings indicate that, in men with heart failure, sildenafil citrate reduces vagal modulation and increases sympathetic modulation, probably through its reflex vasodilatory action. The autonomic system changes induced with sildenafil citrate could alter QT dynamics. Both changes could favor the onset of lethal ventricular arrhythmias. At the dose usually taken for erectile dysfunction, sildenafil citrate has no direct effect on cardiac repolarization (QT interval or dispersion). (Am Heart J 2002;143:703-10.)