Sequence of cardiovascular autonomic alterations after fingolimod initiation.

BACKGROUND: Homeostasis between heart rate and blood pressure is based on several interacting regulatory reflexes, which become influenced by fingolimod initiation. The aim of this study was to determine the sequence of changes in cardiovascular autonomic regulation after fingolimod initiation. METHODS: Twenty-seven patients with relapsing-remitting multiple sclerosis underwent continuous electrocardiogram recording during the first 6 hr after the first dose of fingolimod. In addition to the time interval between two consecutive R-peaks (RR interval), blood pressure and heart rate variability (HRV) were measured on hourly basis. Cardiac parasympathetic and sympathetic regulation were assessed by the different components of HRV. RESULTS: HRV demonstrated an enhancement in cardiac parasympathetic regulation starting 1 hr after the first dose of fingolimod. Blood pressure started to decrease 2 hr and sympathetic cardiac regulation 3 hr after fingolimod initiation. Recovery in RR interval, systolic and diastolic blood pressure, as well as in cardiac autonomic regulation started after 5 hr postdose, whereas pulse pressure (difference between systolic and diastolic blood pressure) continued to increase at the time of hospital discharge. CONCLUSIONS: RR interval, blood pressure, as well as the parasympathetic and sympathetic components of cardiac autonomic regulation alter sequentially in different temporal pattern after fingolimod initiation. These findings enhance the understanding of the effects of fingolimod initiation on cardiovascular autonomic regulation in real life.

Effect of fingolimod on cardiac autonomic regulation in patients with multiple sclerosis.

BACKGROUND: Fingolimod modulates sphingosine-1-phosphate receptors that are also found in cardiovascular tissue. OBJECTIVE: To investigate the effects of fingolimod on cardiac autonomic regulation prospectively. METHODS: Twenty-seven relapsing-remitting multiple sclerosis patients underwent 24-hour electrocardiogram recording before, at the first day of fingolimod treatment (1d) and after three months of continuous dosing (3mo). The time interval between two consecutive R-peaks (RR-interval) was measured. Cardiac autonomic regulation was assessed by the various parameters of heart rate variability. Parasympathetic stimulation prolongs the RR-interval and increases heart rate variability while the effects of sympathetic stimulation are mainly the opposite. The low frequency/high frequency ratio reflects sympathovagal balance. RESULTS: From baseline to 1d, a prolongation of the RR-interval (P<0.001), an increase in the values of various heart rate variability parameters (P<0.05 to P<0.001) and a decrease in the low frequency/high frequency ratio (P<0.05) were demonstrated. At 3mo, although the RR-interval remained longer (P<0.01), the values of various heart rate variability parameters were lower (P<0.01 to P<0.001) as compared to baseline. At 3mo, the low frequency/high frequency ratio (P<0.05) was higher in men than in women although no such difference was found at baseline or at 1d. CONCLUSIONS: After an initial increase in parasympathetic regulation, continuous fingolimod dosing shifts cardiac autonomic regulation towards sympathetic predominance, especially in men. Careful follow-up of fingolimod-treated relapsing-remitting multiple sclerosis patients is warranted as sympathetic predominance associates generally with impaired outcome.ClinicalTrials.cov: NCT01704183.

Heart rate variability associates with asymptomatic coronary atherosclerosis.

PURPOSE: Heart rate variability (HRV) becomes impaired in symptomatic coronary artery disease (CAD), particularly, after myocardial infarction. The mechanism how CAD results in impairment of cardiac autonomic regulation is not known. Whether it results rather from coronary atherosclerosis itself than myocardial ischemia and myocardial injury has remained elusive. METHODS: Quantitative coronary angiography was performed in 30 subjects without history of myocardial ischemia, but with high familial risk for CAD. HRV was measured from 24-h ambulatory ECG recordings in time and frequency domain and also non-linear HRV variables SD1 and SD2 in Poincare plot were calculated. Myocardial ischemia was excluded by Tc-99m sestamibi scintigraphy at rest and during exercise. RESULTS: Coronary angiography revealed mean diameter stenosis of 32 ± 19 % in left anterior descending coronary artery, 26 ± 16 % in left circumflex coronary artery and 25 ± 20 % in right coronary artery. An inverse correlation was found between pNN50 and global severity of coronary artery diameter stenosis (r = -0.415, p < 0.05). Correspondingly, power of HF spectral component correlated negatively with global extent of coronary atherosclerosis (r = -0.366, p < 0.05). In Poincare plot, SD1/SD2 ratio correlated with global extent (r = -0.394, p < 0.05) and global burden (r = -0.388, p < 0.05) of coronary arteries. CONCLUSIONS: The severity and extent of coronary atherosclerosis were related to a shift of cardiac autonomic regulation towards sympathetic predominance in asymptomatic subjects without evidence of myocardial ischemia.

Effect of middle cerebral artery territory ischemic stroke on QT interval.

BACKGROUND: Prolonged QT interval associates with increased risk for sudden cardiac death after acute ischemic stroke. However, pathophysiology of prolonged QT interval after stroke is poorly elucidated. In this study, we investigated whether QT interval dynamics is different in patients with right and left middle cerebral artery (MCA) territory stroke. METHOD: Electrocardiogram (ECG) intervals were compared between baseline (retrieved retrospectively from medical records) and admission (acquired at the acute hospital admission) in 33 patients (65 ± 9.5 years) with right or left MCA territory ischemic stroke. Head computed tomography (CT), cardiac ultrasound, and cardiac CT scans were undertaken. RESULTS: Stroke was located in the right MCA territory in 21 (64%) and in the left MCA territory in 12 (36%) patients. Patients with right and left MCA stroke were similar with respect to time interval between baseline and admission ECG recordings, positive history of heart disease, and left ventricular dimensions. Increase in heart rate-corrected QT interval (QTc) from baseline to admission was demonstrated to occur more often in patients with right (16 of 21; 76%) than in patients with left (3 of 12; 25%; P < .01) MCA stroke. ΔQTc between baseline and admission was significantly longer in patients with right (23 ± 23 milliseconds) than in patients with left (-11 ± 19 milliseconds; P < .0001) MCA stroke. Percent ΔQTc between baseline and admission was longer in patients with right (5.5% ± 5.5%) than in patients with left (-2.6% ± 4.7%; P < .001) MCA stroke. CONCLUSIONS: Right MCA ischemic stroke results in prolongation of QT interval. Findings indicate cerebral asymmetry in brain-heart interaction during acute ischemic stroke.

[Pressure ulcer and tetanus in an elderly person]. / Vanhuksen painehaava ja jäiykkäkouristus.

Clostridium tetani, the bacterium causing tetanus, can be found both in the soil and intestinal normal flora. While the majority of the Finnish population has adequate vaccination protection, part of the population exhibits weakened protection. We describe a case in which a patient developed tetanus as a consequence of pressure ulcer. The symptoms extended to the respiratory muscle region, resulting in respiratory insufficiency and cardiac arrest for the patient. The patient, however, recovered after successful resuscitation and extended intensive care as required by tetanus.

Fatigue and health-related quality of life depend on the disability status and clinical course in RRMS.

BACKGROUND: Fatigue is a prominent and disabling symptom of multiple sclerosis (MS), impairing quality of life. The disease course of relapsing remitting MS (RRMS) is individual. OBJECTIVES: We aimed to study the effects of demographic and clinical characteristics, as well as lifestyle risk factors on experienced fatigue and health-related quality of life (HRQoL) among RRMS patients, comparing benign and severe disease types. METHODS: Altogether 198 Finnish RRMS patients were recruited for this real-life cross-sectional study. Self-reported questionnaires were used to evaluate fatigue and HRQoL by using Fatigue Scale for Motor and Cognitive Functions and 15D health-related quality of life questionnaires. Patients were categorized into subgroups based on the current disability status measured by the Expanded Disability Status Scale (EDSS) cut-off value of 4.5, and by retrospective clinical course divided into benign and aggressive RRMS. RESULTS: All in all, 73% of the RRMS patients suffered from fatigue. Lower HRQoL had a strong correlation with more prominent fatigue (r = -0.719). Higher EDSS was associated with more prominent fatigue and lower HRQoL in the whole RRMS cohort. Older age at the disease onset was associated with more prominent fatigue and decreased HRQoL in the groups of aggressive RRMS and EDSS > 4.5. In the groups of EDSS ≤ 4.5 and benign RRMS, a higher number of used disease-modifying treatments (DMTs) was associated with more pronounced fatigue and reduced HRQoL. In addition, higher BMI was associated with lower HRQoL in patients with benign RRMS. Side effects (45 %) and lack of efficacy (26 %) were the most common reasons for discontinuing a DMT. Cessation due to side effects was the only reason that was significantly associated with more prominent fatigue and lower HRQoL. Use of nicotine products, gender, or disease duration were not associated with fatigue or HRQoL. CONCLUSIONS: Individuals with severe RRMS and higher EDSS scores are more prone to experience fatigue and lower HRQoL. In addition, fatigue and lower HRQoL are more commonly observed among RRMS patients with older age at disease onset and in those with multiple DMT switches.

Myocardial (123) I-metaiodobenzylguanidine washout and heart rate variability in asymptomatic subjects.

BACKGROUND: Myocardial (123) I-metaiodobenzylguanidine (MIBG) kinetics reflect the integrity and function of cardiac presynaptic sympathetic nerve terminals. Heart rate variability (HRV) is an indicator of cardiac sympatho-vagal balance. However, the function of cardiac sympathetic nerve terminals as a modulator of HRV in asymptomatic subjects has remained elusive. In addition, the physiological background for different components of HRV is not fully established. METHODS: We evaluated the relationship between myocardial MIBG washout and HRV in 30 asymptomatic subjects with familial risk of coronary artery disease (CAD). Early and delayed myocardial MIBG uptakes as well as MIBG washout between these two scans were assessed. Myocardial perfusion at rest and during bicycle exercise was evaluated with (99m) Tc-sestamibi (MIBI). HRV was measured from 24-hour ambulatory ECG recordings. RESULTS: Myocardial MIBG washout averaged 40 ± 8%. The mean heart rate at rest was 76 ± 14 beats/min. Standard deviation of all normal RR intervals (SDNN) was 94 ± 22 ms and very low frequency (VLF) was 1625 ± 958 ms(2) on average. Myocardial MIBG washout correlated inversely with SDNN (r =-0.390; P < 0.05) and with VLF (r =-0.459; P < 0.01) component of HRV but not with heart rate at rest (r = 0.207, P = ns). All subjects had normal myocardial perfusion at rest and during exercise. CONCLUSIONS: Increased cardiac presynaptic sympathetic nervous activity was related to reduced HRV in subjects with the risk of CAD but without evidence of myocardial ischemia or previous myocardial infarction. In addition, we found that VLF component of HRV includes information about sympathetic neural modulation of the heart rate.

[Hypoglossal nerve palsy]. / Miksi kieli ei käänny?--kielen liikehermon halvaus.

Dysfunction of the hypoglossal nerve (nervus hypoglossus) occurs usually as part of a larger symptom complex, only rarely being the sole symptom of a neurologic disorder. Peripheral etiology must also be kept in mind, especially in patients with malignant primary disease. We describe a patient who developed an isolated right hypoglossal nerve palsy, which later became bilateral. In computerized tomography the bones of the cranial base of the patient with prostatic cancer were damaged by metastases especially in the vicinity of hypoglossal canals.

Grey matter atrophy in patients with benign multiple sclerosis.

BACKGROUND: Brain atrophy appears during the progression of multiple sclerosis (MS) and is associated with the disability caused by the disease. METHODS: We investigated global and regional grey matter (GM) and white matter (WM) volumes, WM lesion load, and corpus callosum index (CCI), in benign relapsing-remitting MS (BRRMS, n = 35) with and without any treatment and compared those to aggressive relapsing-remitting MS (ARRMS, n = 46). Structures were analyzed by using an automated MRI quantification tool (cNeuro®). RESULTS: The total brain and cerebral WM volumes were larger in BRRMS than in ARRMS (p = .014, p = .017 respectively). In BRRMS, total brain volumes, regional GM volumes, and CCI were found similar whether or not disease-modifying treatment (DMT) was used. The total (p = .033), as well as subcortical (p = .046) and deep WM (p = .041) lesion load volumes were larger in BRRMS patients without DMT. Cortical GM volumes did not differ between BRRMS and ARRMS, but the volumes of total brain tissue (p = .014) and thalami (p = .003) were larger in patients with BRRMS compared to ARRMS. A positive correlation was found between CCI and whole-brain volume in both BRRMS (r = .73, p < .001) and ARRMS (r = .80, p < .01). CONCLUSIONS: Thalamic volume is the most prominent measure to differentiate BRRMS and ARRMS. Validation of automated quantification of CCI provides an additional applicable MRI biomarker to detect brain atrophy in MS.

Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients.

BACKGROUND: Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. OBJECTIVES: To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. METHODS: In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. RESULTS: Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. CONCLUSIONS: SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

Serum GFAP and NfL levels in benign relapsing-remitting multiple sclerosis.

OBJECTIVE: We aimed to investigate serum glial fibrillary acidic protein (GFAP) and serum neurofilament light chain (NfL) levels as potential discriminative biomarkers between benign relapsing-remitting multiple sclerosis (BRRMS) and aggressive relapsing-remitting MS (ARRMS). METHODS: Serum GFAP and NfL levels were analyzed in patients with BRRMS (n = 34), ARRMS (n = 29), and healthy controls (n = 14) by using Single Molecule Array (Simoa). Patients with ARRMS had been treated with highly effective disease-modifying treatments (DMT) (fingolimod or natalizumab). RESULTS: Serum GFAP levels in both BRRMS (median 210.19 pg/ml, IQR 163.69-287.19) and in ARRMS (median 188.60 pg/ml, IQR39.23-244.93) were significantly higher (p = 0.035 and p = 0.034, respectively) compared to healthy controls (median 117.93 pg/ml, IQR 60.28-183.83). Serum GFAP levels did not differ between BRRMS and ARRMS. There were no statistical differences in NfL levels between BRRMS, ARRMS and healthy controls. GFAP level was significantly higher (p = 0.04) in BRRMS without DMT (median 216.04 pg/ml, IQR 188.60-274.79) than in those BRRMS patients who had used DMT (median 196.26 pg/ml, IQR 133.33-325.54). CONCLUSIONS: We found elevated levels of serum GFAP in both BRRMS and ARRMS compared to healthy controls, reflecting astrocytic activation. Serum NfL did not differ between BRRMS and ARRMS, probably due to the stable inflammatory phase of the disease and effective DMT use in ARRMS. Single serum NfL and GFAP measurements cannot separate a patient with BRRMS from effectively treated ARRMS after a long history of the disease, thus consecutive samples are needed in the follow-up.

Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation.

BACKGROUND: Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting. METHODS: We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse. RESULTS: At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0% and 35.6% of patients, whereas corticosteroid-treated relapses were documented in 20.2% and 30.3% of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p < 0.001) and at 12 months (HR 1.53, p < 0.001). Expanded Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p = 0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p = 0.019) or second-line therapies (HR 3.94, p = 0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation. CONCLUSION: High disease activity and a high level of disability prior to NTZ treatment seem to predict disease reactivation after treatment cessation. When switching to subsequent DMDs, the washout time should not exceed 3 months. However, subsequent DMDs failed to prevent the reactivation of MS in this cohort.

[Malignant cerebral infarction and hemicraniectomy]. / Hemikraniektomia pahanlaatuisen aivoinfarktin hoidossa.

BACKGROUND: Malignant cerebral infarction has 80% mortality rate that could be decreased by hemicraniectomy. MATERIAL AND METHODS: We retrospectively evaluated medical records of all 12 consecutive patients who underwent hemicraniectomy due to malignant cerebral infarction in Kuopio university hospital between 2003 and 2/2009. RESULTS: Infarction affected left hemisphere in 4/12 patients and right hemisphere in 8/12 patients. 50% of the patients (6/12) survived. Operation delay was not associated with outcome. Systolic blood pressure in acute phase was significantly lower in survivors as compared to non-survivors (126 +/- 8 mmHg vs 154 +/- 12 mmHg, p < 0.001, respectively). CONCLUSIONS: Selected patients with malignant cerebral infarction benefit from hemicraniectomy.

Cardiac repolarization evolves differently during the course of benign and disabling multiple sclerosis.

BACKGROUND: Cardiac repolarization is modulated by the autonomic nervous system. Even though multiple sclerosis associates with prolonged cardiac repolarization the physiology responsible for the phenomenon remains unknown. OBJECTIVE: To study in longitudinal setting whether the patients with confirmed benign and disabling outcome of relapsing-remitting multiple sclerosis (RRMS) differ in regard to changes of cardiac repolarization. METHODS: Total of 43 patients, 26% with benign (EDSS ≤2 at least 10y after onset symptom) and 74% with disabling (EDSS >2 at least 10y after onset symptom) RRMS, having 12-lead electrocardiogram (ECG) recorded at the time of onset symptom (ECG1) and for follow-up (ECG2), were studied. Heart rate (HR) corrected QT intervals (QTc) reflecting cardiac repolarization were assessed. RESULTS: The time interval between ECG1 and ECG2 showed no statistical difference between benign (7.8 ± 4.8y) and disabling (10.2 ± 5.6y; p = .211) RRMS. Patients with benign and disabling RRMS showed similar values of HR (66±9 bpm vs 73 ± 15 bpm; p=.146) and QTc (403 ± 13 ms vs 408 ± 19 ms; p = .450) at the time of ECG1. However, at the time of ECG2, HR was higher (79 ± 14 bpm vs 65 ± 10 bpm; p = .004) and QTc was longer (420 ± 24 ms vs 400 ± 15 ms; p = .012) in patients with disabling than benign RRMS. Correspondingly, HR increased (p = .063) and QTc prolonged (p = .014) during the disease course only in patients with disabling RRMS. CONCLUSIONS: Deterioration of cardiac autonomic regulation during the disease course associates with disabling but not with benign RRMS. Our findings suggest that assessment of cardiac autonomic regulation should be included in the evaluation of RRMS disease course. In addition, patients with disabling RRMS might be prone to unfavorable cardiovascular outcome also due to deterioration of autonomic nervous system.

Cardiac repolarization during fingolimod treatment in patients with relapsing-remitting multiple sclerosis.

Background: Fingolimod is a sphingosine-1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite an established effect on heart rate, the effect of fingolimod on cardiac repolarization is not completely known. Methods: Twenty-seven patients with RRMS underwent 24-hr ambulatory ECG before fingolimod (baseline), at the day of fingolimod initiation (1D) and after three-month treatment (3M). The mean values of RR-interval as well as QT-interval corrected by Bazzet's (QTcBaz) and Fridericia's (QTcFri) formula were compared between baseline, 1D, and 3M over 24-hr period as well as at daytime and nighttime. Results: QTcBaz over 24-hr was shorter at 1D (414 ± 20 ms, p < .001) and at 3M (414 ± 20 ms, p < .001) than at baseline (418 ± 20 ms). In contrast, QTcFri over 24-hr was longer at 1D (410 ± 19 ms, p < .001) but similar at 3M (406 ± 19 ms, p = .355) compared to baseline (407 ± 19 ms). Daytime QTcBaz was shorter at 1D (p < .001) and at 3M (p = .007), whereas daytime QTcFri was longer at 1D (p < .05) but similar at 3M (p = ns) compared to baseline. During the night, changes were observed neither in QTcBaz nor in QTcFri between baseline, 1D, and 3M. Conclusions: Changes in cardiac repolarization after fingolimod initiation were mild and occurred at daytime. Ambiguously, QTcBaz demonstrated shortening, whereas QTcFri showed prolongation in cardiac repolarization after fingolimod initiation. The formula applied for QT-interval correction needs to be taken carefully into account as evaluating pharmacovigilance issues related to fingolimod.

The impact of multiple sclerosis onset symptom on cardiac repolarization.

INTRODUCTION: Multiple sclerosis is associated with prolonged cardiac repolarization but the underlying physiology has remained unknown. In this study, we compared cardiac repolarization during the relapsing-remitting multiple sclerosis (RRMS) disease course in patients with motor and sensory onset symptom. METHODS: Twenty-five RRMS patients with motor and 33 RRMS patients with sensory onset symptom having 12-lead electrocardiogram (ECG) recorded at the time of the first demyelinating event (ECG1) as well as at the later disease course (ECG2) were identified from the patient records. The average time interval between ECG1 and ECG2 was 8.6 ± 5.9 y. Heart rate-corrected QT intervals reflecting cardiac repolarization were calculated by Bazett (QTcBaz), Fridericia (QTcFri), and Karjalainen (QTcKar) formulas. RESULTS: Heart rate-corrected QT intervals as well as heart rate were similar in patients with motor and sensory onset symptom in ECG1. However, QTcBaz (p = .002), QTcFri (p = .019), and QTcKar (p = .026) were longer and heart rate was higher (p = .035) in patients with motor than sensory onset symptom in ECG2. Correspondingly, QTcBaz (p = .002), QTcFri (p = .033), and QTcKar (p = .043) prolonged and heart rate tended to increase (p = .060) during the disease course only in the patients with motor onset symptom. CONCLUSIONS: Cardiac repolarization prolonged and heart rate increased during the disease course in RRMS patients with motor but not with sensory onset symptom. This suggests different traits in RRMS according to its initial manifestation and also association of motor onset symptom with more unfavorable cardiovascular prognostic determinants.

Heart rate variability predicts the magnitude of heart rate decrease after fingolimod initiation.

BACKGROUND: Fingolimod is an immunomodulator with a disease modifying effect on relapsing-remitting multiple sclerosis (RRMS). A heart rate (HR) decrease shortly after fingolimod initiation, however, requires a clinical vigilance. The aim of this study was to prospectively investigate whether cardiac autonomic regulation can predict the magnitude of HR decrease after fingolimod initiation. METHODS: Twenty-five patients with RRMS underwent ambulatory 24-h electrocardiogram recording to assess HR variability 20±16 days before fingolimod initiation (baseline) and repeated at the day of fingolimod initiation to assess the magnitude of HR decrease. The percentage of normal RR-intervals with duration more than 50ms different from the previous normal RR-interval (pNN50) was calculated (among the other HR variability parameters) to assess cardiac autonomic regulation. The maximal HR decrease (ΔHR) after the first dose of fingolimod was assessed in absolute units (beats/min) and in percentage (%). RESULTS: The maximal ΔHR was -20±11 beats/min (-23±12%) on the average. pNN50 calculated at baseline correlated with ΔHR% (r=-0.657, p<0.001). A HR decrease ≥20% was found in 10/14 patients with pNN50≥10%. The positive and negative predictive values of pNN50≥10% to predict ΔHR≥20% were 83% and 69%, respectively leading to accuracy of 76%. CONCLUSIONS: Cardiac autonomic regulation (pNN50>10%) at baseline can be used to predict the magnitude of HR decrease after the first dose of fingolimod. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01704183).

Modulation of sphingosine receptors influences circadian pattern of cardiac autonomic regulation.

Fingolimod is an oral sphingosine-1-phospate (S1P) receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). In addition to therapeutic effects on lymphoid and neural tissue, fingolimod influences cardiovascular system by specific S1P-receptor modulation. The effects of S1P-receptor modulation on the endogenous circadian pattern of cardiac autonomic regulation (CAR), however, are not known. We examined the effects of fingolimod on the circadian pattern of CAR Ambulatory 24-h ECG recordings were undertaken in 27 RRMS patients before fingolimod (baseline), at the day of fingolimod initiation (1D) and after 3 months of fingolimod treatment (3M). The mean time between two consecutive R-peaks (RR-interval) and mean values for measures of heart rate variability (HRV) in time- and frequency domain were calculated from ECG recording at daytime and nighttime. The mean night:day-ratio of RR-interval was 1.23 ± 0.12 at baseline, decreased temporarily at 1D (1.16 ± 0.12; P < 0.01) and was higher at 3M (1.32 ± 0.11; P < 0.001) than at baseline. The night:day-ratio of HRV parameters reflecting parasympathetic cardiac regulation (pNN50, rMSSD, HFnu) decreased at 1D but recovered back to baseline at 3M (P < 0.05 for all). On the other hand, the night:day-ratio of TP, a parameter reflecting overall HRV gradually decreased and was lower at 3M than at baseline (P < 0.05). Our findings suggest that physiological relation between the circadian pattern of RR-interval and overall HRV as well as parasympathetic cardiac regulation becomes uncoupled during fingolimod treatment. In addition, fingolimod shifts the circadian equilibrium of CAR toward greater daytime dominance of overall HRV Accordingly, S1P-receptor modulation influences circadian pattern of CAR.

Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT).

BACKGROUND: Catheter-based intracoronary vascular endothelial growth factor (VEGF) gene transfer is a potential treatment for coronary heart disease. However, only limited data are available about local VEGF gene transfer given during angioplasty (PTCA) and stenting. METHODS AND RESULTS: Patients with coronary heart disease (n=103; Canadian Cardiovascular Society class II to III; mean age, 58+/-6 years) were recruited in this randomized, placebo-controlled, double-blind phase II study. PTCA was performed with standard methods, followed by gene transfer with a perfusion-infusion catheter. Ninety percent of the patients were given stents; 37 patients received VEGF adenovirus (VEGF-Adv, 2x10(10) pfu), 28 patients received VEGF plasmid liposome (VEGF-P/L; 2000 microg of DNA with 2000 microL of DOTMA:DOPE [1:1 wt/wt]), and 38 control patients received Ringer's lactate. Follow-up time was 6 months. Gene transfer to coronary arteries was feasible and well tolerated. The overall clinical restenosis rate was 6%. In quantitative coronary angiography analysis, the minimal lumen diameter and percent of diameter stenosis did not significantly differ between the study groups. However, myocardial perfusion showed a significant improvement in the VEGF-Adv-treated patients after the 6-month follow-up. Some inflammatory responses were transiently present in the VEGF-Adv group, but no increases were detected in the incidences of serious adverse events in any of the study groups. CONCLUSIONS: Gene transfer with VEGF-Adv or VEGF-P/L during PTCA and stenting shows that (1) intracoronary gene transfer can be performed safely (no major gene transfer-related adverse effects were detected), (2) no differences in clinical restenosis rate or minimal lumen diameter were present after the 6-month follow-up, and (3) a significant increase was detected in myocardial perfusion in the VEGF-Adv-treated patients.