Heart Rate Variability in Huntington Disease: A Long-Term Longitudinal Study.

INTRODUCTION: The aim of the study was to follow tonic and phasic autonomic nervous activity in Huntington disease (HD) mutation carriers and patients. METHODS: Evaluation of motor functions and total functional capacity was performed in 30 HD mutation carriers or patients at the beginning and in 22 subjects after 8-10 years. Continuous arterial blood pressure, heart rate (HR), and ECG at rest were measured, and HR variability analysis was performed in four different ways. A group of matched controls was also evaluated. RESULTS: Eighteen subjects were assorted in 3 groups: 6 HD mutation carriers without motor symptoms (PHD) who remained so (PHD-PHD); 6 early symptomatic patients (EHD) who remained so (EHD-EHD); and 6 early symptomatic patients who deteriorated to a late symptomatic (LHD) (EHD-LHD). At the beginning, sympathetic tonic activity in PHD was elevated, according to mean arterial pressure (99 ± 10.6 mm Hg) higher than in controls (85 ± 8.7 mm Hg) and EHD (82 ± 9.9 mm Hg) (Dunnett's test, p < 0.05) and higher HR (78 ± 16 beats/min) than after 8-10 years (64 ± 11.3 beats/min) (paired t test, p < 0.05). There was also a decreased phasic sympathetic activity in EHD patients compared controls at the beginning (219 ± 106 vs. 664 ± 466 s2/Hz) and after 8-10 years (182 ± 136 vs. 1,012 ± 1,369 s2/Hz) (Dunnett's test, p < 0.05). In patients who deteriorated from EHD to LHD, there was a drop in phasic parasympathetic activity from 887 ± 433 to 230 ± 235 s2/Hz (paired t test, p < 0.05). CONCLUSIONS: Our long-term observational study provides important information on the timeline of ANS activity in HD progress. There was a temporary increase in cardiac and vascular sympathetic activity in PHD subjects. The normalization of HR in PHD subjects might indicate the approach of an outbreak of clinical disease phase.

The effect of caffeine on cutaneous postocclusive reactive hyperaemia.

BACKGROUND: Caffeine is reported to be the most widely used pharmacologically active substance. It causes mental stimulation and increases blood pressure. Acute systolic and diastolic blood pressure response to caffeine attenuates in the course of regular caffeine use; tolerance to cardiovascular responses develops in some people. For some hypertension-prone people coffee ingestion may be harmful, and for others it may be beneficial. The aim of our work was to evaluate the effect of caffeine on postocclusive reactive hyperaemia (PORH), a test of microvascular function, and at the same time to monitor the central effects of caffeine on blood pressure and heart rate. METHODS: Heart rate, arterial pressure, and cutaneous laser-Doppler (LD) flux were monitored in 32 healthy volunteers (aged 25.2 ± 4.3 years) before and after they ingested 200 mg of caffeine. LD flux was measured on a finger at rest and after the release of an 8-minute occlusion of digital arteries above the place of LD flux measurement. All parameters obtained after the ingestion of caffeine were compared to the values obtained before caffeine and to the values obtained after a placebo. RESULTS: We found slightly increased arterial pressure as well as decreased heart rate and resting LD flux (Dunnett's test, p<0.05) after the ingestion of caffeine. Caffeine significantly reduced the PORH response (Dunnett's test, p<0.01). The power of the low-frequency oscillations (0.06-0.15 Hz) of LD flux, representing vascular myogenic activity, increased significantly after the ingestion of caffeine at rest and during the PORH response. A correlation was found between the number of cups of coffee regularly consumed and resting LD flux values (R = 0.492, p = 0.00422), peak LD flux values during PORH (R = 0.458, p = 0.00847), and the PORH area (R = 0.506, p = 0.00313) after caffeine consumption. CONCLUSIONS: From the results, we can conclude that caffeine affects cutaneous microvascular function during rest and during a PORH response, and that it increases blood pressure and decreases heart rate.

Evidence of cardiac electrical remodeling in patients with Huntington disease.

OBJECTIVE: Although Huntington's disease (HD) is a disease of the central nervous system, HD mortality surveys indicate heart disease as a major cause of death. Cardiac dysfunction in HD might be a primary consequence of peripherally expressed mutant huntingtin or secondary to either a general decline in health or the onset of neurological dysfunction. The aim of the study was to clarify the heart muscle involvement. MATERIALS AND METHODS: We measured conventional and advanced resting ECG indices. Thirty-one subjects with a confirmed huntingtin gene mutation and 31 age- and gender-matched controls were included. The HD subjects were divided into four groups based on their Unified Huntington Disease Rating Scale (UHDRS) motor score. RESULTS: We detected changes in advanced ECG variables connected with electrical ventricular remodeling (t test, p < 0.01). The increase in the unexplained part of both QT variability and the standard deviation of normal-to-normal QT intervals, presumably reflecting beat-to-beat changes in repolarization, was most pronounced. Further, both variables correlated with the product of the cytosine-adenine-guanine (CAG) triplets' repeat length and the subjects' age (CAP), the former R = 0.423 (p = 0.018) and the latter R = 0.499 (p = 0.004). There was no correlation between the CAP score and any of variables representing autonomic nervous system activity. CONCLUSIONS: Both autonomic nervous system dysfunction and cardiac electrical remodeling are present in patients with HD. The changes in advanced ECG variables observed in the study evolve with HD progression. The increased values of QT unexplained variability may be a marker of temporal inhomogeneity in ventricular repolarization associated with malignant ventricular arrhythmias.

L-arginine as dietary supplement for improving microvascular function.

BACKGROUND: Reduced availability of nitric oxide leads to dysfunction of endothelium which plays an important role in the development of cardiovascular diseases. OBJECTIVE: The aim of the present study was to determine whether the dietary supplement L-arginine improves the endothelial function of microvessels by increasing nitric oxide production. METHODS: We undertook experiments on 51 healthy male volunteers, divided into 4 groups based on their age and physical activity since regular physical activity itself increases endothelium-dependent vasodilation. The skin laser Doppler flux was measured in the microvessels before and after the ingestion of L-arginine (0.9 g). The endothelium-dependent vasodilation was assessed by acetylcholine iontophoresis and the endothelium-independent vasodilation by sodium nitroprusside iontophoresis. In addition, we measured endothelium-dependent and endothelium-independent vasodilation in 81 healthy subjects divided into four age groups. RESULTS: After the ingestion of L-arginine, the endothelium-dependent vasodilation in the young trained subjects increased (paired t-test, p < 0.05), while in the other groups it remained the same. There were no differences in the endothelium-independent vasodilation after ingestion of L-arginine. With aging endothelium-independent vasodilation decreased while endothelium-dependent vasodilation remained mainly unchanged. CONCLUSION: Obtained results demonstrated that a single dose of L-arginine influences endothelium-dependent vasodilation predominantly in young, trained individuals.

Functional impairment of precerebral arteries in Huntington disease.

BACKGROUND: Cardiovascular pathology of Huntington disease (HD) appears to be complex; while microvascular dysfunction seems to appear early, deaths from cardiomyopathy and stroke might occur in the late phase of HD. METHODS: Our study evaluated global risk factors for coronary heart disease (CHD), structure and function of precerebral arteries in 41 HD subjects and 41 matched controls. HD subjects were divided into groups by the United Huntington disease rating scale (presymptomatic-PHD, early-EHD, midstage-MHD and late-LHD). CHD risk factors assessment and Doppler examination of precerebral arteries were performed, including measurements of the carotid artery intima-media thickness (IMT), and parameters indicating local carotid artery distensibility (stiffness index ß, pulse wave velocity, pressure strain elasticity module and carotid artery compliance). RESULTS: In the HD and controls we identified a comparable number of non-obstructive plaques (<50% lumen narrowing). No obstructive plaques (>50% lumen narrowing) were found. There was significantly increased IMT in MHD. In PHD and EHD the parameters of arterial stiffness were significantly higher and the carotid artery compliance was significantly lower. CONCLUSIONS: Our results reveal functional vascular pathology in PHD, EHD, and MHD. Precerebral arteries dysfunction in HD therefore appears to be mostly functional and in agreement with recently described autonomic nervous system changes in HD.

Diazepam augments gender differences in cutaneous LD flux response to local cooling.

Cutaneous vasoconstriction in response to local cooling is normally greater in females than in males. Cold induces amplification of alpha2-adrenoceptor affinity for norepinephrine and increases reflex sympathetic thermoregulatory output. Benzodiazepines are drugs with very well-known binding to the central and peripheral benzodiazepine receptors. Besides these effects they decrease sympathetic output and as it was shown in the last decade they act synergistically with alpha-adrenoceptors. In the present study we tested the hypothesis that the benzodiazepine diazepam interacts with an alpha-adrenoceptor mechanism at the level of microcirculation. We measured laser-Doppler blood flux changes provoked by local cooling before and after oral application of a low dose of diazepam (5 mg) in 9 healthy males and in 11 healthy females with regular menstrual cycles. The results of our experiments show that in females there is a significant reduction (ANOVA, p < 0.05) in laser-Doppler flux during the first four minutes of cooling after taking of diazepam. In males, there is no significant difference in the responses to cold before and after an application of diazepam. Our results suggest that diazepam, in addition to its well-known effect on BZ receptors may also interact with alpha2C-adrenoceptors in the vessel wall during local cooling.

Effect of transcutaneous application of gaseous carbon dioxide on cutaneous microcirculation.

BACKGROUND: The inefficient healing of chronic wounds is a result of poor blood perfusion at the wound and surrounding tissues. Artificially applied carbon dioxide (CO2) has the potential to improve the perfusion and oxygenation of tissues, hence is useful for the healing of chronic wounds. OBJECTIVE: The aim of the present study was to determine the effect of a transcutaneous application of physiological vasodilator gaseous CO2 on cutaneous blood flow. METHODS: Laser Doppler (LD) flux in cutaneous microcirculation, skin temperature, electrocardiogram and arterial blood pressure were measured simultaneously in a group of 33 healthy men, aged 21-28 years, during rest and a 35-minute CO2 therapy. One lower limb of each subject represented the studied extremity, being exposed to gaseous CO2. The contralateral limb was the control, being exposed to air. Each limb was sealed in a plastic bag. RESULTS: During CO2 therapy the LD flux in the studied extremity increased from 5.8 PU ± 3.9 PU to 30.3 PU ± 16.7 PU (mean ± standard deviation; paired t-test, p <  0.001), while that in the control extremity did not change significantly. CONCLUSIONS: Our results confirm a local vasodilatory effect of applied CO2 therapy. This finding indicates its potential clinical use.

The influence of quantal content on the time course of the endplate current in frogs.

The aim of this study was to find out whether control and facilitated endplate current (EPC) of a curarized frog nerve-muscle preparation stimulated with paired impulses decay at the same time constant. The experiments revealed that the decay of the greater second EPC was slower in nearly half of the cases. This half of the results suggests that a larger quantity of the released transmitter and, consequently, a higher density of open channels promote a cooperative effect among them. The end effect can be a longer mean lifetime of open acetylcholine channels. In the other half of the experiments, the mean lifetime of open channels seems to be independent of the agonist concentration.

Cognitive and autonomic dysfunction in presymptomatic and early Huntington's disease.

Huntington's disease is characterized by disorders of movement, cognition and behavior. Individuals with Huntington's disease display aberrant changes in the autonomic nervous system that are detected even before the onset of other symptoms. Subtle cognitive dysfunction may start before other clinical manifestations. The aim of the present study was to investigate the autonomic nervous system response to mental arithmetic and the relationship between the autonomic and cognitive/motor function in presymptomatic and early Huntington's disease. We examined 15 presymptomatic Huntington's disease gene carriers (PHD), 15 early Huntington's disease patients (EHD) and 30 healthy controls. PHD and EHD groups were determined according to Unified Huntington's Disease Rating Scale (UHDRS) motor score. ECG, heart rate, systolic and diastolic blood pressure, and cutaneous laser Doppler flux were measured during rest and during a simple mental arithmetic test. UHDRS cognitive test battery was applied to determine cognitive dysfunction. During mental arithmetic, the heart rate of PHD/EHD increased significantly less than that of controls. Decreased microvascular response to mental arithmetic was found in EHD. Significant correlations for the PHD/EHD group were found between laser Doppler flux response and Symbol Digit Modalities Test score, and between laser Doppler flux response and UHDRS motor score. It seems that central autonomic dysregulation of cardiovascular system in Huntington's disease goes along with the degeneration of other central neuronal systems. This finding is relevant as it could enable simple and noninvasive testing of disease progression.

Microcirculation response to local cooling in patients with Huntington's disease.

Altered autonomic nervous system (ANS) functioning in early stages of Huntington's disease (HD) has been suggested, presumably due to distorted high-order autonomic control. ANS functioning in the early stages of HD was further investigated. Laser-Doppler (LD) flux in the skin of the fingertips, heart rate (HR), HR variability, systolic and diastolic blood pressure were measured during rest and during a 6 min cooling of one hand at 15°C. Data of 15 presymptomatic gene mutation carriers (PHD), 15 early symptomatic HD patients (EHD), and two groups of 15 age- and sex-matched controls were compared. The area under the low frequency (LF) and high frequency (HF) bands of the HR variability spectrum were calculated. An augmented reduction of cutaneous LD flux was found in response to the direct cooling in the PHD group (37.5 ± 8.5% of resting value) compared to the PHD controls (67.27 ± 8.4%) (p < 0.05). In addition, the PHD group had higher (LF/(LF + HF) index of primary sympathetic modulation of the HR at rest (53.6 ± 3.3) compared to the EHD patients (39.7 ± 4.2) (p < 0.05). In the EHD group, a significantly smaller change of HR during cooling (100.26 ± 1.2%) was found compared to the EHD controls (95.9 ± 1.0%) (p < 0.05). The results are in line with the hypothesis that ANS dysfunction occurs even in PHD subjects. Further, they support the hypothesis that dysfunction of the high-order autonomic centres are involved in HD.