Alexandra Pintér

Autonomic Dysregulation in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, progressive central neurological disease characterized by inflammation and demyelination. In patients with MS, dysregulation of the autonomic nervous system may present with various clinical symptoms including sweating abnormalities, urinary dysfunction, orthostatic dysregulation, gastrointestinal symptoms, and sexual dysfunction. These autonomic disturbances reduce the quality of life of affected patients and constitute a clinical challenge to the physician due to variability of clinical presentation and inconsistent data on diagnosis and treatment. Early diagnosis and initiation of individualized interdisciplinary and multimodal strategies is beneficial in the management of autonomic dysfunction in MS. This review summarizes the current literature on the most prevalent aspects of autonomic dysfunction in MS and provides reference to underlying pathophysiological mechanisms as well as means of diagnosis and treatment.

Carotid artery stiffness is not related to endothelial function in young healthy subjects

INTRODUCTION Carotid artery stiffness, an important determinant of arterial baroreflex sensitivity, varies considerably in healthy individuals, the source of which variability is not known. Tonic relaxant influence of the endothelium on vascular smooth muscle, reducing stiffness of the vessel wall, has been established in muscular conduit arteries. It is not known to what extent stiffness of the elastic carotid artery is under endothelial control. SUBJECTS AND METHODS Seventy-one healthy male volunteers were studied. Endothelial function was assessed by brachial artery flow mediated dilatation (FMD) normalized by diastolic shear rate (SRd). Carotid artery elastic parameters were determined by echo wall-tracking and tonometry. Systemic arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV). RESULTS In univariate analysis carotid artery elastic parameters were related to BMI and systolic blood pressure, but were not related to any of endothelial function parameters. As expected, PWV was related inversely to nFMD. No relation was found between vascular stiffness parameters and endothelium-independent dilation (EID). CONCLUSION Carotid artery elasticity in health is not related to conduit artery FMD, suggesting that endothelial influence on baroreceptor activity is not exerted through changes in barosensory wall elasticity.

Adaptation of baroreflex function to increased carotid artery stiffening in patients with transposition of great arteries

We have shown previously that TGA (transposition of great arteries) is associated with increased carotid artery stiffness. It has been established that stiffening of the barosensory vessel wall results in reduced baroreceptor activation and impaired BRS (baroreflex sensitivity). In the present study we tested the hypothesis that the increased carotid artery stiffness in TGA patients was associated with reduced cardiovagal BRS. We studied 32 TGA patients aged 9-19 years, 12+/-3 years after surgical repair and 32 age-matched healthy control subjects. Carotid artery diastolic diameter and pulsatile distension was determined by echo wall tracking; carotid blood pressure was measured by tonometry. BRS was measured using spontaneous techniques [BRS(seq) and LF(gain) (low-frequency transfer function gain)] and by the phenylephrine method (BRS(phe)). Carotid artery distensibility was markedly reduced in patients as compared with controls (5.6+/-1.9 x 10(-3) compared with 8.7+/-2.7 x 10(-3)/mmHg P<0.05, as determined using an unpaired Students t test), but BRS was not different in patients and controls (20.3+/-14.7 compared with 21.7+/-12.7 for BRS(seq); 13.1+/-9.2 compared with 10.6+/-4.5 for LF(gain); and 19.1+/-8.6 compared with 24.8+/-7.2 for BRS(phe) respectively). Carotid artery elastic function was markedly impaired in patients with TGA, but the increased stiffness of the barosensory vessel wall was not associated with reduced BRS. It appears that attenuation of baroreceptor stimulus due to arterial stiffening may be compensated by other, possibly neural, mechanisms when it exists as a congenital abnormality.

Neuropsychiatric symptoms in untreated parkinson’s disease

Neuropsychiatric and cognitive symptoms are common in Parkinson’s disease (PD) and may precede and exceed motor symptoms as major factors impacting disease course and quality of life. Neuropsychiatric symptoms (NPS) in PD are various and are attributed to pathologic changes within multiple brain regions, to psychological stress, and to adverse effects of dopamine replacement therapy. Sleep disorders and mood symptoms such as apathy, depression, and anxiety may antedate the development of motor symptoms by years, while other NPS such as impulse control disorders, psychosis, and cognitive impairment are more common in later stages of the disease. Few studies report on NPS in the early, untreated phase of PD. We reviewed the current literature on NPS in PD with a focus on the early, drug-naive stages of PD. Among these early disease stages, premotor and early motor phases were separately addressed in our review, highlighting the underlying pathophysiological mechanisms as well as epidemiological characteristics, clinical features, risk factors, and available techniques of clinical assessment.

Impaired baroreflex function is related to reduced carotid artery elasticity in patients with tetralogy of Fallot

Sudden cardiac death (SCD) is a common late complication in patients with tetralogy of Fallot (ToF). Reduced baroreflex sensitivity (BRS) is an independent predictor of SCD and BRS reduction was reported in ToF. Relationship between BRS and carotid artery distensibility (DC) in healthy subjects was reported by us earlier. We also found that DC was reduced in ToF patients. In the present study we tested the hypothesis that reduced BRS is related to increased carotid artery stiffness. We studied 36 ToF patients (21±11 years) and 60 age-matched healthy control subjects. Intravenous phenylephrine-induced (BRSphe) and spontaneous (BRSseq) BRS indices were derived. DC calculation was based on echo wall-tracking and tonometry. BRS indices were reduced in patients compared with controls (BRSphe 16.8±10.2 vs. 27.3±9.2ms/mmHg; BRSseq 9.3±9.2 vs. 18.3±7.8ms/mmHg). DC was also lower in patients (5.1±1.8 vs. 6.3±2.610(-3)/mmHg). BRS correlated with DC across patients and controls (BRSphe r=0.75 vs. r=0.74; BRSseq r=0.44 vs. r=0.38). Multiple regression analysis indicated that BRS indices are determined independently by DC in ToF patients. We showed that reduced DC may contribute to impaired baroreflex function in ToF patients and could in part explain the elevated risk for SCD postoperatively. Therefore it would be an important future investigation to test carotid artery stiffness and analyze its predictive value for cardiac mortality in ToF. Preventive actions to impede carotid artery stiffening should receive more attention in the clinical management of ToF patients.

Genetic impact dominates over environmental effects in development of carotid artery stiffness: A twin study

Arterial stiffness is an independent predictor of cardiovascular, cerebrovascular and all-cause mortality. Quantifying the genetic influence on the stiff arterial phenotype allows us to better predict the development of arterial stiffness. In this study, we aimed to determine the heritability of carotid artery stiffness in healthy twins. We studied 98 twin pairs of both sexes. We determined carotid artery stiffness locally using echo tracking and applanation tonometry. We estimated the heritability of stiffness parameters using structural equation modeling. The carotid distensibility coefficient showed the highest heritability (64%, 95% confidence interval 45–77%). The incremental elastic modulus, compliance and stiffness index β also showed substantial heritability (62%, 61% and 58%, respectively). The remaining 36–42% phenotypic variance was attributed to unshared environmental effects. Genetic influence appears to dominate over environmental factors in the development of carotid artery stiffness. Environmental factors may have an important role in favorably influencing the genetic predisposition for accelerated arterial stiffening.

Relationship between heart rate variability and endothelial function in healthy subjects

In various diseased states reduced cardiac vagal activity is accompanied by impaired endothelial function. Evidence from animal studies indicates interaction between the two systems, but such data from human studies is limited. The aim of this study was to test the hypothesis that cardiac vagal activity and endothelial function are related in healthy individuals. 46 young males were studied. From 10 minute long ECG recordings mean RR-interval and time and frequency domain vagal heart rate variability indices (RMSSD; pNN50 and HF, respectively) were determined. Heart rate variability indices were used to define cardiac vagal activity. Endothelial function was assessed by measuring brachial artery flow mediated dilation. Hyperemic, diastolic shear rate was used to normalize flow mediated dilation. All three vagal heart rate variability indices correlated significantly and positively with flow mediated dilation across subjects, with r values within the range of 0.43-0.52, p<0.01 for all relations. After adjusting for potential confounders, vagal heart rate variability indices remained significantly associated with normalized flow mediated dilation. RR-interval was related to most heart rate variability indices, but was not related to flow mediated dilation. Our data demonstrate that vagal heart rate variability indices are related to flow mediated dilation across healthy male subjects. The results cannot serve as evidence of a causal relationship, but are of interest and render for further investigation into underlying mechanisms.

Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson’s Disease (CAPTURE PD): Protocol for a Multicenter Study

Background In Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function. Methods/design A prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation. Discussion We anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha-synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD. Clinical trail registration TRN NCT03043768.