Genome-wide linkage scan for quantitative trait loci underlying normal variation in heel bone ultrasound measures.

Quantitative ultrasound (QUS) traits are correlated with bone mineral density (BMD), but predict risk for future fracture independent of BMD. Only a few studies, however, have sought to identify specific genes influencing calcaneal QUS measures. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing normal variation in QUS traits. QUS measures were collected from a total of 719 individuals (336 males and 383 females) from the Fels Longitudinal Study who have been genotyped and have at least one set of QUS measurements. Participants ranged in age from 18.0 to 96.6 years and were distributed across 110 nuclear and extended families. Using the Sahara ® bone sonometer, broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (QUI) were collected from the right heel. Variance components based linkage analysis was performed on the three traits using 400 polymorphic short tandem repeat (STR) markers spaced approximately 10 cM apart across the autosomes to identify QTL influencing the QUS traits. Age, sex, and other significant covariates were simultaneously adjusted. Heritability estimates (h²) for the QUS traits ranged from 0.42 to 0.57. Significant evidence for a QTL influencing BUA was found on chromosome 11p15 near marker D11S902 (LOD = 3.11). Our results provide additional evidence for a QTL on chromosome 11p that harbors a potential candidate gene(s) related to BUA and bone metabolism.

Longitudinal changes in calcaneal quantitative ultrasound measures during childhood.

UNLABELLED: This longitudinal study examined how calcaneal quantitative ultrasound (QUS) measures change during childhood while taking into account skeletal maturation, body mass index (BMI), and physical activity. The study reported sex differences in QUS growth curves and an inverse relationship between BMI and speed of sound (SOS) measures. INTRODUCTION: The aim of this study was to examine how calcaneal QUS parameters change over time during childhood and to determine what factors influence these changes. METHODS: The study sample consisted of a total of 192 Caucasian children participating in the Fels Longitudinal Study. A total of 548 calcaneal broadband ultrasound attenuation (BUA) and SOS observations were obtained between the ages of 7.6 and 18 years. The best fitting growth curves were determined using statistical methods for linear mixed effect models. RESULTS: There are significant sex differences in the pattern of change in QUS parameters (p < 0.05). The relationship between QUS measures and skeletal age is best described by a cubic growth curve in boys and a linear pattern among girls. Boys experience their most rapid growth in BUA and SOS in early and late adolescence, while girls experience constant growth throughout childhood. Adiposity levels were significantly associated with the changes in SOS among boys (p < 0.001) and girls (p < 0.01), indicating that children with higher BMI are likely to have lower SOS over time compared to children with lower BMI. For girls, physical activity levels showed positive associations with changes in QUS measures (p < 0.05). CONCLUSION: This study documents significant sex differences in the pattern of change in QUS measures over childhood and adolescence. Our study also shows significant influences of adiposity and physical activity on the pattern of change in QUS measures during childhood.

Sleep disturbance in relation to health-related quality of life in adults: the Fels Longitudinal Study.

OBJECTIVE: Sleep disturbances are prevalent problems in the general population. Symptoms of insomnia can impact various physical and mental conditions. Furthermore, sleep disturbances may worsen the quality of life independently of co-occurring medical conditions. In this study, we examined the relationships between self-reported sleep disturbance symptoms and health-related quality of life measures in the Fels Longitudinal Study. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 397 adults (175 men and 222 women) aged 40 years and older were included in the present study. MEASUREMENTS: Three self-reported sleep disturbance measures (difficulty falling asleep, nocturnal awakenings and maintaining sleep, and daytime tiredness) were collected between 2003 and 2006. Health-related quality of life measures were assessed using the Medical Outcomes Survey Short Form (SF)-36. Socio-demographic status (marital status, employment status, and education) and current medical conditions were collected from participants during study visits. RESULTS: Individuals who reported frequent sleep disturbances showed significantly worse quality of life on all SF-36 subscales examined. The odds ratio (OR) ranged from 1.71 to 18.32 based on symptoms of insomnia across seven SF-36 domains in analyses adjusted for significant covariates influencing quality of life. Participants with severe sleep disturbances (both sleep problems and daytime impairment) showed generally higher odds of reporting poor SF-36 scores (adjusted ORs; 5.88 - 17.09) compared to participants with no problems. CONCLUSION: Sleep disturbance is comprehensively and independently associated with poor health-related quality of life in middle-aged and older adults.

The first seriatim study into old age for weight, stature and BMI: the Fels Longitudinal Study.

PURPOSE: To document the serial status of measures of weight, stature and BMI from birth into old age. METHODS: Longitudinal measures of weight, stature and BMI were taken from birth to 76 years of age for 5 men and 7 women as part of the Fels Longitudinal Study. RESULTS: Sex-specific plots of means for weight, stature and BMI are presented that describe the changes and sex differences in these measurements between birth (or the first year of life) into old age. These serial data demonstrate a continuous increase in body weight through much of adulthood and a small decline in stature starting in late middle age. The plots for BMI indicate the early onset of overweight and subsequent obesity early in adulthood and its continuance into old age for men and women. CONCLUSIONS: These are the first plots of serial means for weight, stature and BMI measured from the same group of individuals from birth into old age. These findings demonstrate the changes in these measurements through childhood and maturity into old age. Similar data are needed for individuals from other racial/ethnic groups and countries in order to understand the aging process better.

Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1).

OBJECTIVE: This study was performed to identify a possible relationship between genotype and phenotype in the congenital familial long QT syndrome (cLQTS). BACKGROUND: The cLQTS, which occurs as an autosomal dominant or recessive trait, is characterized by QT-interval prolongation on the electrocardiogram and torsade de pointes arrhythmias, which may give rise to recurrent syncope or sudden cardiac death. Precipitators for cardiac events are exercise or emotion and occasionally acoustic stimuli. METHODS: The trigger for cardiac events (syncope, documented cardiac arrhythmias, sudden cardiac death) was analyzed in 11 families with a familial LQTS and a determined genotype. RESULTS: The families were subdivided in KVLQT1-related families (LQTS1, n = 5) and HERG (human ether-a-gogo-related gene)-related families (LQTS2, n = 6) based on single-strand conformation polymorphism analysis and sequencing. Whereas exercise-related cardiac events dominate the clinical picture of LQTS1 patients, auditory stimuli as a trigger for arrhythmic events were only seen in LQTS2 patients. CONCLUSIONS: Arrhythmic events triggered by auditory stimuli may differentiate LQTS2 from LQTS1 patients.

Mitral valve prolapse and ventricular arrhythmias: observations in a patient with a 20-year history.

INTRODUCTION: Ventricular arrhythmias are a common feature in patients with mitral valve prolapse. In an attempt to determine the origin and underlying electrophysiologic mechanism, we describe a patient with ventricular fibrillation, exercise-induced ventricular tachycardia (VT), and, at the time of diagnosis, prolapse of the posterior mitral valve leaflet without mitral regurgitation. METHODS AND RESULTS: Treatment with beta-blockade and diphenylhydantoin prevented the occurrence of malignant ventricular arrhythmias for more than 17 years. Discontinuation of the therapy resulted in an immediate reappearance of the VT, which, despite the marked enlargement of the left ventricle (secondary to development of severe mitral valve regurgitation), had a strikingly similar morphology. For hemodynamic reasons, the patient was finally selected for valve replacement. Detailed pre-, peri-, and postoperative studies were performed, including administration of flunarizine, body surface mapping, construction of perioperative epicardial and endocardial maps, and studies of the excised muscles in vitro. CONCLUSIONS: Delayed afterdepolarization-induced triggered activity is the mechanism of VT in this mitral valve prolapse patient. The trigger is provided by isolated ventricular premature complexes elicited by a different electrophysiologic mechanism, possibly reentry, which is related to stretch and presumably to fibrosis of the papillary muscles.

[Aging and cardiology; various physiological, pathophysiological and clinical aspects]. / Veroudering en cardiologie; enkele fysiologische, pathofysiologische en klinische aspecten.

The main cardiovascular effect of aging is a rise of the systolic blood pressure due to reduced impedance of the central arteries. The resulting increase of the afterload leads to hypertrophy, increased rigidity and lengthening of the relaxation period in the left ventricle. The manifestations of ischaemia or arrhythmias are often atypical at more advanced ages and may delay diagnosis. Ejection murmur due to stenosis of the aortic valve, to calcification or degeneration, may be difficult to distinguish from a functional murmur. The cause of heart failure is usually coronary sclerosis and, less often, hypertension or a valvular defect. Systolic heart failure is associated with decreased contractility of the left ventricle and compensatory dilation, diastolic heart failure with reduced filling of the ventricles. Both forms respond well to acute treatment with antihypertensive, diuretic and (or) vasodilator drugs; the treatment in isolated diastolic heart failure should also focus on lowering the increased blood pressure and reducing the heart rate to increase the filling phase.

[Heart failure in a Ghanese woman due to endomyocardial fibrosis]. / Hartfalen bij een Ghanese vrouw ten gevolge van endomyocardfibrose.

Endomyocardial fibrosis was diagnosed in a 30-year-old Ghanese woman suffering from heart failure and intracardial thrombi. Endomyocardial fibrosis is an endemic disease in tropical countries with a high mortality rate. Since the aetiology of this disease is still unknown, patients can only be treated symptomatically. Endocardial and myocardial damage give rise to reactive fibrosis, subendocardial infarction and thrombus formation, resulting in heart failure and thromboembolic processes.

Long-term antiarrhythmic efficacy and safety of d-sotalol in patients with ventricular tachycardia and a low ejection fraction.

Since in patients with ventricular tachycardia (VT) and compromised left ventricular function, antiarrhythmic therapy poses a particular problem, an open-label safety study of d-sotalol, a new class III antiarrhythmic agent, was performed. Thirteen patients with defined VT and a low left ventricular ejection fraction (LVEF) were treated with orally administered d-sotalol, 100 mg bid, and in a few patients 100 mg tid, in an open study. Patients were followed up for 35 +/- 11 months, with the longest follow-up amounting to 51 months. The data obtained suggest that d-sotalol was moderately effective as an antiarrhythmic agent, in particular with respect to premature ventricular contractions (PVCs) and coupled and repetitive PVCs. The beneficial effect appeared to persist on long-term treatment. d-Sotalol was well tolerated and no subjective or objective adverse reactions were observed. There were no signs of worsening of congestive heart failure, proarrhythmogenic activity, or torsades de pointes, although QT-prolongation was observed. There were no dropouts in the study. Two patients died: One patient with idiopathic dilated cardiomyopathy (with LVEF = 11%) died suddenly after 38 months of follow-up and one patient after 17 months from recurrent myocardial infarction. Neither of these had shown recurrence of VT on 24 hour ambulatory ECG recordings. In conclusion, in this small group of patients d-sotalol appeared to be safe and well tolerated during long-term treatment of patients with VT and poor left ventricular function. There were clear suggestions of antiarrhythmic activity, reflected by the suppression of complex ventricular arrhythmias and by the absence of recurrent VT on long-term follow-up in the majority of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Two cases of amiodarone-induced thyrotoxicosis successfully treated with a short course of antithyroid drugs while amiodarone was continued.

Two patients with amiodarone-induced thyrotoxicosis were treated successfully with potassium perchlorate and carbimazole while treatment with amiodarone was continued. These antithyroid drugs were stopped after the patients had became clinically and biochemically euthyroid. During follow up, when treatment with amiodarone continued, thyrotoxicosis did not recur. Amiodarone-induced thyrotoxicosis seems to be a transient condition that can be treated successfully with a short course of antithyroid drugs without stopping amiodarone treatment.

Effects of changes in management of active infective endocarditis on outcome in a 25-year period.

The clinical outcome and long-term follow-up of 130 consecutive patients (141 episodes) with active infective endocarditis who were treated between 1966 and 1991 were analyzed. There was a shift toward a higher proportion of referred patients (39 to 78%), patients aged > 60 years (11 to 41%) and urgent surgical treatment (11 to 44%). Medical treatment was administered in 98 patients (70%); 30-day mortality was 27%. Surgery was performed in 43 patients (30%), with an operative mortality of 26%; 9 of 14 patients (64%) who underwent operation within the first week of admission died. Patients with severe heart failure are at the highest risk for early mortality (relative risk = 21.1; 95% confidence interval 7.4-60.3). Referred patients were much more often treated surgically than were nonreferred patients (48 versus 14%) and had a lower operative mortality (24 vs 30%). Nonreferred patients were more often treated medically (86 vs 52%) and with lower mortality (19 vs 39%). The total follow-up time was 730 patient-years; only 1 patient was considered lost to follow-up. The overall cumulative 5-year and 10-year survival after hospital discharge for patients after urgent surgery were 84 +/- 7% and 53 +/- 7%, respectively, and for those after medical treatment 84 +/- 5% and 77 +/- 6%, respectively. The probability of remaining free of late events (recurrent endocarditis, late valve replacement or death) during 5 and 10 years for patients after urgent surgery was 84 +/- 7% and 53 +/- 15%, respectively, and for those after medical treatment 59 +/- 6% and 40 +/- 7%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The value of Doppler echocardiography in the management of patients with valvular heart disease: analysis of one year of clinical practice.

Management recommendations based on Doppler echocardiographic examination and cardiac catheterization were compared in a prospective study in 100 consecutive patients who were admitted for evaluation and treatment of suspected valvular heart disease during 1988. Management recommendations were provided independently after both Doppler echocardiography and cardiac catheterization by different and blinded investigators. Criteria for severe (clinically significant) and moderate to mild (insignificant) valvular lesions and management recommendations were agreed on in advance. There was disagreement on the severity of aortic stenosis based on the aortic valve area and maximum instantaneous pressure gradient in 1 of 54 patients, which resulted in differing management recommendations. Mitral stenosis was severe (valve area less than or equal to 1 cm2) at Doppler echocardiography but not at cardiac catheterization in 5 of 14 patients. Because pulmonary artery pressure increase during exercise at cardiac catheterization also suggested severe obstruction, management recommendations were similar. There was a potentially significant disagreement on the severity of aortic regurgitation in 9 of 76 patients and of mitral regurgitation in 14 of 90 patients; however, this did not produce differing management recommendations because with most patients coexistent valvular lesions or an impaired ventricular function mainly determined the ultimate management decision. Although of good quality, Doppler echocardiographic examination was nonconclusive for clinical decision-making in 15% of the study population because of uncertainty about the severity of mitral regurgitation or aortic regurgitation or because of problems in assessing the degree of left ventricular dysfunction in patients with severe regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Sarcoidosis of the heart]. / Sarcoïdose van het hart.

In 2 patients arrhythmias and conduction disorders were the first symptoms at presentation of cardiac sarcoidosis. One patient with severe conduction disorders showed normalisation of the EKG during steroid treatment. The other patient developed an overall cardiomyopathy and the arrhythmia was treated with conventional drugs. The frequency of cardiac involvement in sarcoidosis is much higher than that of clinical symptoms of sarcoid heart disease. Cardiac sarcoidosis is increasingly diagnosed in the last few decades. In most cases, it presents with sudden death, arrhythmia, conduction disorders or cardiomyopathy. The main diagnostic pathological feature is evidence of noncaseating granulomas, but mononuclear cell infiltration and focal interstitial fibrosis have also been found. The basal part of the interventricular septum is particularly prone to involvement. If conventional therapy in clinically important cases proves inadequate, steroid therapy should be added. It is recommended to make an EKG in every patient presenting with sarcoidosis even in the absence of cardiac symptoms. Sarcoid heart disease should be considered in every patient with diagnostic sarcoidosis and heart disease but also in every case of difficult heart disease without an obvious aetiology. Because of the relatively early age at onset, life expectancy is shortened.

Changes in skin blood flow during the menstrual cycle: the influence of the menstrual cycle on the peripheral circulation in healthy female volunteers.

1. It is known that females have a lower skin perfusion than males. In women there are also differences in blood flow at different reproductive stages of their lives. As an initial investigation of the possible contribution of sex hormones to these differences, we studied skin and forearm blood flow during the natural changes in hormone levels which occur during the menstrual cycle. 2. Thirty-one healthy female volunteers were studied. The effect of a standardized finger cooling test (immersion of a gloved hand in a 16 degrees C water bath) on finger skin temperature and on laser Doppler flux in the finger, and forearm blood flow (strain gauge venous occlusion plethysmography) was assessed at four different times during one cycle: during menstruation, 1 day before ovulation, 2 days after ovulation and at the mid-luteal phase. Test days were determined by daily measurements of basal body temperature and were confirmed afterwards by determinations of serum luteinizing hormone, follicle-stimulating hormone, 17 beta-oestradiol and progesterone. 3. Peripheral skin circulation varied significantly within one menstrual cycle. The extremes were a mean finger skin temperature of 25.9 +/- 3.0 degrees C in the luteal phase compared with 28.4 +/- 3.7 degrees C in the pre-ovulatory phase (P = 0.002). The respective values for the mean laser Doppler flux were 18.4 +/- 10.9 compared with 29.2 +/- 16.4 arbitrary units (P = 0.003). 4. Baseline forearm muscle blood flow also varied significantly (P = 0.04) within one menstrual cycle, with low values in the menstrual phase compared with the other phases.(ABSTRACT TRUNCATED AT 250 WORDS)