Pre-operative baroreflex sensitivity and efferent cardiac parasympathetic activity are correlated with post-operative pain.

BACKGROUND: A maladaptation of the autonomic nervous system may been seen in patients with chronic pain that includes persistent changes in the autonomic tone, increased heart rate, and reduced heart rate variability and baroreflex sensitivity. Baroreflex sensitivity and acute pain intensity have been reported to be inversely correlated. However, it is unknown whether the same correlation applies with regard to post-operative pain. In the present study, autonomic function was measured in patients scheduled for minor hand surgery and correlated with early and persistent pain after the procedure. Thus, the cause (autonomic imbalance) was present before the effect (post-operative pain). Our primary hypothesis was that a lower level of pre-operative baroreflex sensitivity is correlated with increased early post-operative pain. METHODS: There were 30 patients included and scheduled for open carpal tunnel surgery. Baroreflex sensitivity and heart rate variability were measured before surgery. Efferent cardiac parasympathetic activity was estimated by power spectral analysis of heart rate variability. Post-operative pain was recorded daily for 6 weeks (early post-operative pain) and for 1 week 1 year after surgery (persistent post-operative pain). RESULTS: Pre-operative baroreflex sensitivity correlated negatively with early (P=0.05) and persistent (P=0.04) post-operative pain. Efferent cardiac parasympathetic activity correlated negatively with early (P=0.03) but not persistent post-operative pain (P=0.12). CONCLUSIONS: The findings suggest that a low pre-operative level of baroreflex sensitivity is associated with higher post-operative pain intensity. To our knowledge, this is the first study to show the correlation between baroreflex sensitivity and post-operative pain.

Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms.

Mutations in the gene for desmoplakin (DSP) may cause arrhythmogenic right ventricular cardiomyopathy (ARVC) and Carvajal syndrome (CS). Desmoplakin is part of all desmosomes, which are abundantly expressed in both myocardial and epidermal tissue and serve as intercellular mechanical junctions. This study aimed to investigate protein expression in myocardial and epidermal tissue of ARVC and CS patients carrying DSP mutations in order to elucidate potential molecular disease mechanisms. Genetic investigations identified three ARVC patients carrying different heterozygous DSP mutations in addition to a homozygous DSP mutation in a CS patient. The protein expression of DSP in mutation carriers was evaluated in biopsies from myocardial and epidermal tissue by immunohistochemistry. Keratinocyte cultures were established from skin biopsies of mutation carriers and characterized by reverse transcriptase polymerase chain reaction, western blotting, and protein mass spectrometry. The results showed that the mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue. The investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans.

Cardiac involvement in juvenile neuronal ceroid lipofuscinosis (Batten disease).

OBJECTIVE: To explore the onset and progression of cardiac involvement in juvenile neuronal ceroid lipofuscinosis (JNCL). METHODS: The study population comprised an unselected group of 29 children and adolescents with genetically verified JNCL. We focused on T-wave abnormalities on an EKG, cardiac hypertrophy, and left ventricular systolic function on echocardiography, and heart rates and heart rate variability (HRV) on 24-hour EKG recordings. The surviving patients were observed for 7½ years. The 24-hour EKG recording was repeated after 3 years. RESULTS: Abnormally deeply inverted T waves were present in one-third of the initial EKG recordings and were reported as early as 14 years of age. We found coherence between the presence of repolarization disturbances of the ventricular myocardium at the initial recordings and risk of death during the observation period. At increasing age, heart rate and HRV, expressed as the vagal index (number of adjacent RR intervals deviating more than 6%), were significantly reduced, suggesting an age-dependent bidirectional effect of JNCL on heart rate: one through decreasing parasympathetic activity on the heart and the other through a direct negative influence on sinus node automaticity. Coherence between bradycardia and arrhythmia and occurrence of sinus arrests and atrial flutter with increasing age indicated an age-dependent decrease in sinus node activity also. In the early 20s, a high frequency of ventricular hypertrophy occurred. CONCLUSIONS: Progressive cardiac involvement with repolarization disturbances, ventricular hypertrophy, and sinus node dysfunction occur in JNCL. We recommend that the attention on heart involvement in JNCL and other neuronal ceroid lipofuscinosis subtypes should be intensified.

Effects of metoprolol on QT interval and QT dispersion in Type 1 diabetic patients with abnormal albuminuria.

AIMS/HYPOTHESIS: The excess mortality in diabetes is mainly due to cardiovascular causes and almost confined to patients with abnormal albuminuria. Compared to healthy subjects, diabetic patients have a prolonged QT interval and increased QT dispersion. In non-diabetic subjects, as well as in Type 1 diabetic patients with overt nephropathy, a prolonged QT interval and increased QT dispersion are associated with cardiac morbidity and mortality. There is an increasing number of studies on effects of beta blocker treatment on QT interval and QT dispersion in non-diabetic subjects. In contrast, there are no studies on the effects of beta blocker treatment on QT interval and QT dispersion in patients with diabetes. The aim of our study was to describe the effects of metoprolol treatment on QT interval and QT dispersion in a group of well-characterised Type 1 diabetic patients with elevated urine albumin excretion. METHODS: We studied the effects of 6 weeks of treatment with metoprolol (100 mg once daily, zero order kinetics formulation) in a randomised, placebo-controlled, double blind, crossover trial including 20 Type 1 diabetic patients. Patients were simultaneously monitored under ambulatory conditions with 24-h Holter-monitoring, 24-h ambulatory blood pressure recording and 24-h fractionated urine collections. On days of investigation 12-lead electrocardiograms were recorded and autonomic tests performed. RESULTS: We found strong associations between both daytime and night-time blood pressure and heart-rate-corrected QT interval dispersion (QTc dispersion). Heart rate variability parameters indicating sympathetic and parasympathetic modulation showed strong correlations with heart-rate-corrected QT interval (QTc interval) and with QTc dispersion. Beta blocker treatment caused a decrease in QTc interval but no change in QTc dispersion. CONCLUSIONS/INTERPRETATION: This study is the first to address the QTc interval and QTc dispersion in Type 1 diabetic patients treated with metoprolol. Beta blocker treatment caused a decrease in QTc interval but no change in QTc dispersion. These results may in part explain the pronounced cardioprotective effect of beta blocker treatment in diabetic patients with cardiovascular disease.

Mental stress inhibits pain perception and heart rate variability but not a nociceptive withdrawal reflex.

AIM: Do distraction from- or attention to sural nerve stimulation affect pain, heart rate variability, and a spinal withdrawal reflex? MATERIAL AND METHODS: In 26 male volunteers, electrical stimulation at the distal cutaneous receptive field of the sural nerve elicited pain and a nociceptive withdrawal reflex. Intensity of pain was rated on a numeric rating scale. Electromyographic reflex responses were measured from biceps femoris muscle. Cardiac autonomic function was estimated by heart rate variability measures and was expressed in the time domain as mean of RR-intervals for normal heart beats (mean-RR) and standard deviation of all normal RR-intervals (SD-NN) and, in the frequency domain, where pure vagal activity was assessed by high frequency power (0.15-0.4 Hz). Low frequency power (0.04-0.15 Hz) reflects both parasympathetic and sympathetic control. Effect parameters were recorded before and during random distraction and attention. Distraction from sural nerve stimulation was induced by a mental arithmetic test, paced auditory serial addition task (PASAT), while attention was induced by concentrating on painful foot stimulation. RESULTS: Paced auditory serial addition task decreased mean-RR and SD-NN, frequency domain parameters, as well as pain (P<0.001). In contrast, PASAT did not change the spinal withdrawal reflex. Attention did not affect any effect parameter. CONCLUSION: Distraction by PASAT altered autonomic activity and inhibited pain but failed to affect withdrawal reflex responses, while attention had no effect on either parameter. Psychological distraction and attention may have different effects on noxious evoked pain perception and autonomic activity. Pain relief during PASAT probably involves supraspinal mechanisms.

Cardiac troponin levels following monitored epileptic seizures.

Cardiac arrhythmia associated with myocardial injury is a proposed mechanism for sudden unexplained death in epilepsy. The authors measured serial cardiac troponin levels in 11 patients after monitored seizures. Using highly sensitive assays and criteria, no troponin elevations were seen, indicating that myocardial injury does not occur during uncomplicated seizures. An elevation in postictal troponin elevations should suggest the presence of cardiac injury secondary to neurocardiogenic mechanisms or primary cardiac factors, prompting further evaluation.

Evidence of cardiac ischemia during seizures in drug refractory epilepsy patients.

The authors investigated whether patients with drug refractory epilepsy have cardiovascular abnormalities that might be related to a high frequency of sudden death. Twenty-three subjects underwent comprehensive cardiovascular evaluations before and during video-EEG monitoring. ST-segment depression occurred in 40% and was associated with a higher maximum heart rate during seizures. These data suggest that cardiac ischemia may occur in these patients.

Atrio-ventricular block: a possible explanation of sudden unexpected death in epilepsy.

INTRODUCTION: This is the third case report describing the occurrence of total atrio-ventricular (AV)-block as a life threatening cardiac arrhythmia complicating epileptic seizures. CASE REPORT: A 56-year-old right-handed man was admitted to our hospital for surgical assessment of his medically intractable epilepsy. During the hospitalization he was enrolled in a study investigating cardiac complication of epileptic seizures as the possible cause of sudden unexplained death among epileptics. DISCUSSION: To the best of our knowledge, we are the first to employ simultaneous video-electroencephalogram-, Holter- and pulse oximetry-recordings of our patients in the description of this complication. These recordings allowed us to discuss the evidence and consequences of this particular cardiac abnormality as an explanation of sudden unexplained death in epileptic seizures, especially those of temporal origin.

Effects on heart rate variability of metoprolol supplementary to ongoing ACE-inhibitor treatment in Type I diabetic patients with abnormal albuminuria.

AIMS/HYPOTHESIS: Diabetic nephropathy is associated with a high risk of cardiac mortality including sudden death. This is presumably related to an imbalance between sympathetic and parasympathetic tone resulting in a decreased heart rate variability (HRV). In non-diabetic patients a decreased HRV is known to be a strong predictor of cardiovascular death. Studies in non-diabetic patients have shown that beta-blockers improve HRV parameters known to reflect parasympathetic function. The aim of our study was to investigate effects of additional beta-blocker treatment on: cardiac autonomic function, blood pressure, and urine albumin excretion in ACE-inhibitor treated Type I (insulin-dependent) diabetes mellitus patients with abnormal albuminuria. METHODS: We studied the effects of 6 weeks treatment with metoprolol (100 mg once daily, zero order kinetics formulation) in 20 patients participating in a randomised, placebo controlled, double blind, crossover trial. Patients were simultaneously monitored under ambulatory conditions with 24-h Holter-monitoring, 24-h ambulatory blood pressure recording, and 24-h fractionated urine collections. Heart rate variability was assessed by four different methods; ambulatory HRV analysis was carried out by spectral and time domain analysis, and on days of investigation short-term spectral analysis and bed-side tests were carried out. RESULTS: Metoprolol treatment improved in vagal tone assessed by short-term spectral analysis. The 24-h ambulatory HRV analysis showed improvement in some parameters reflecting vagal function. A minor decrease in daytime diastolic blood pressure was shown, no alterations in diurnal variation of blood pressure or urine albumin excretion were observed. CONCLUSION/INTERPRETATION: These preliminary findings indicate that beta-blocker treatment could improve autonomic function in Type I diabetic patients with abnormal albuminuria and an associated high risk of cardiovascular disease.

[Early clinical exposure--an instant success. The new medical curriculum at the University of Aarhus]. / Tidlig klinik--en øjeblikkelig succes. Beskrivelse of en ny studieordning på Aarhus Universitet.

INTRODUCTION: In the new medical curriculum at the University of Aarhus, a third term, 20-week course focussing on early patient contact was launched. MATERIAL AND METHODS: Nine prototypical and clinically important disease entities each formed the basis of one-week courses covering an introductory clinical lecture, presentation of "paper" cases, and formalised training of pertinent clinical skills. This was integrated with plenaries and group work in physiology pertaining to the disease and the patient cases. In addition, seminars were held in patient-doctor relationships, and environmental and social medicine. Introductory lectures were given on topics, such as medical ethics, taxonomy of diseases, the organisation of hospital-based health care. At the end of the term, the students resided for eight weeks at county hospitals, which do not traditionally participate in pregraduate teaching. Each student followed one particular patient, which formed the basis of a written essay. RESULTS: Early clinical lectures (87 +/- 8%, mean +/- SD) and use of clinical cases (73 +/- 8%) were well received by third term students, and 87% found that the "paper" cases facilitated their understanding of physiology. The evaluation of the hospital training was very positive (rated excellent or good by > 95%). DISCUSSION: We conclude that early introduction to clinical practice is feasible and well received by the students.

Increased QTc dispersion is related to blunted circadian blood pressure variation in normoalbuminuric type 1 diabetic patients.

A reduced nocturnal fall in blood pressure (BP) and increased QT dispersion both predict an increased risk of cardiovascular events in diabetic as well as nondiabetic subjects. The relationship between these two parameters remains unclear. The role of diabetic autonomic neuropathy in both QT dispersion and circadian BP variation has been proposed, but data have been conflicting. The aim of the present study was to describe associations between QT dispersion and circadian BP variation as well as autonomic function in type 1 diabetic patients. In 106 normoalbuminuric (urinary albumin excretion <20 microg/min) normotensive patients, we performed 24-h ambulatory BP (Spacelabs 90207) and short-term (three times in 5 min) power spectral analysis of RR interval oscillations, as well as cardiovascular reflex tests (deep breathing test, postural heart rate, and BP response). No patient had received (or had earlier received) antihypertensive or other medical treatment apart from insulin. In a resting 12-lead electrocardiogram, the QT interval was measured by the tangent method in all leads with well-defined T-waves. The measurement was made by one observer blinded to other data. The QT interval was corrected for heart rate using Bazett's formula. The QTc dispersion was defined as the difference between the maximum and the minimum QTc interval in any of the 12 leads. When comparing patients with QTc dispersion below and above the median (43 ms), the latter had significantly higher night BP (114/67 vs. 109/62 mmHg, P < 0.003/P < 0.001), whereas day BP was comparable (129/81 vs. 127/79 mmHg). Diurnal BP variation was blunted in the group with QTc dispersion >43 ms with significantly higher night/day ratio, both for systolic (88.8 vs. 86.2%, P < 0.01) and diastolic (83.1 vs. 79.5%, P < 0.01) BP. The association between QTc dispersion and diastolic night BP persisted after controlling for potential confounders such as sex, age, duration of diabetes, urinary albumin excretion, and HbA1c. Power spectral analysis suggested an altered sympathovagal balance in patients with QTc dispersion above the median (ratio of low-frequency/high-frequency power: 1.0 vs. 0.85, P < 0.01). In normoalbuminuric type 1 diabetic patients, increased QTc dispersion is associated with reduced nocturnal fall in BP and an altered sympathovagal balance. This coexistence may be operative in the ability of these parameters to predict cardiovascular events.

Reproducibility of QT parameters derived from 24-hour ambulatory ECG recordings in healthy subjects.

AIM: To estimate the reproducibility of QT parameters derived from 24-hour ambulatory ECG recordings. METHOD: Ten healthy volunteers aged 25 to 41 years participated. In two 24-hour ambulatory ECG recordings obtained 1 day apart, the QT interval was measured manually at stable heart rates in approximately 16 periods during daytime and 6 periods during nighttime. The association between the QT and RR interval was described by linear regression for day and nighttime separately and the following QT parameters were calculated: the QT interval at heart rate 60 beats/min during daytime (QT(60)day), slope(day), slope(night), and the difference in QT(60) between day and nighttime (DeltaQT(60)). The QT parameters were assessed four times for each participant to discriminate method inaccuracy from day to day variation. The reproducibility was estimated as the coefficient of repeatability, the relative error, and the ratio between within-subject variability and between-subject variability. RESULTS: The coefficient of repeatability, the relative error and the ratio, respectively, were 19 ms, 1.8% and 0.5 for QT(60)day, 0.076, 21% and 0.68 for slope(day), 0.116, 43% and 1.37 for slope(night), and 37 ms, 325% and 1.19 for DeltaQT(60) when estimating the overall day to day reproducibility. Inaccuracy of QT measurement accounted for approximately 40% of this variation, whereas the error caused by selecting segments was small. CONCLUSION: QT(60)day has a high reproducibility and may with advantage replace the conventional QT interval measured on a resting ECG. To assess QT dynamics, the slope of the regression line during daytime is suitable and the short term reproducibility acceptable for clinical trials. Regarding slope(night) and DeltaQT(60), the variation is high and the parameters should be used with caution.

Heart rate variability in obesity and the effect of weight loss.

To investigate the effects of obesity and weight loss on cardiovascular autonomic function, we examined 28 obese patients referred for weight-reducing gastroplasty, 24 obese patients who received dietary recommendations, and 28 lean subjects. Body weight, blood pressure, and 24-hour urinary norepinephrine excretion were measured, and time and frequency domain indexes of heart rate variability (HRV) were obtained from 24-hour Holter recordings. A measure of long-term HRV, the SD of all normal RR intervals (SDANN), was used as an index of sympathetic activity and the high-frequency (HF) component of the frequency domain, reflecting short-term HRV, as an estimate of vagal activity. All 3 study groups were investigated at baseline, and the 2 obese groups were reexamined at 1-year follow-up. Obese patients had higher blood pressure, higher urinary norepinephrine excretion, and attenuated SDANN and HF values than lean subjects (p <0.01). Obese patients treated with surgery had a mean weight loss of 32 kg (28%), whereas the obese group treated with dietary recommendations remained weight stable (p <0.001). At follow-up the weight-loss group displayed decreases in blood pressure and norepinephrine excretion and showed increments in SDANN and HF values. These changes were significantly greater than those observed in the obese control group (p <0.05). Our findings suggest that obese patients have increased sympathetic activity and a withdrawal of vagal activity and that these autonomic disturbances improve after weight loss.

Increased left ventricular systolic function in insulin dependent diabetic patients with normal albumin excretion.

Alterations in cardiovascular function may be an aetiological factor for the development of microalbuminuria in patients with insulin-dependent diabetes mellitus. We studied cardiac function with echocardiography in relation to the degree of albuminuria in 27 insulin-dependent diabetes mellitus patients and 13 healthy subjects. Patients were grouped according to urinary albumin excretion: <20 microg x min(-1) (normoalbuminuric), and 20 to 200 microg x min(-1) (microalbuminuric). None were or had been treated with cardiovascular drugs. The normoalbuminuric patients had a higher heart rate, mean velocity of circumferential shortening, stroke velocity index (a measure of contractility), and aortic peak velocity than controls. No difference in diastolic function was present. In the microalbuminuric group, the stroke velocity index was comparable to values observed in healthy subjects. The increased systolic performance (heart rate and contractility) may contribute to the renal hyperperfusion and glomerular hyperfiltration observed in insulin-dependent diabetes mellitus patients before the development of micro- and in turn macroalbuminuria. The possible cause effect mechanisms should be further studied, as preventive medical treatment of the hypercontractile heart is possible. In conclusion, cardiac contractility is increased in insulin-dependent diabetes mellitus patients with normoalbuminuria and returns to levels observed in healthy subjects when microalbuminuria develops.

Lymphopain, a cytotoxic T and natural killer cell-associated cysteine proteinase.

Through differential screening of established human leukaemia cell lines, we have identified and molecularly cloned lymphopain, a novel cysteine proteinase of the papain family. Lymphopain exhibits a remarkably restricted cellular pattern of expression, being predominantly expressed in cytotoxic T-lymphocytes and natural killer cells. The human lymphopain locus maps to chromosome 11q13, encodes a polypeptide of 376 amino acids and is conserved in the mouse. Both human and murine forms appear more closely related to protozoan papain-like enzymes than to other mammalian members of the papain family. The cellular distribution of lymphopain expression, together with the functional demonstration of lymphopain-associated proteinase activity in vitro, is suggestive of a role for lymphopain in immune cell-mediated, cell killing.