Profound cardiac conduction delay predicts mortality in myotonic dystrophy type 1.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is known to affect mainly the musculoskeletal system. Early mortality is related to respiratory disease and possibly additional cardiovascular complications. AIMS: To identify possible cardiovascular disturbances that could predict survival of DM1 patients. METHODS: We studied 30 DM1 patients (mean age 41 +/- 13.5 years, range 16-71, 15 women) who were cardiovascularly stable and compared them with 29 controls (mean age 55 +/- 7.8 years, range 42-66, 14 women) using electrocardiography (ECG) and conventional transthoracic echocardiography. The subgroup that survived a follow-up period of 17 years was re-examined using the same protocol. RESULTS: Of the 30 patients, 10 died of a documented respiratory cause and three of acute myocardial incidents. Compared with controls, left ventricular cavity size, corrected to body surface area, was slightly enlarged at end systole (P < 0.05) and hence fractional shortening was reduced (P < 0.01). Nine patients had first-degree heart block and 15 had a QRS duration >90 ms. Of all ECG and echocardiographic measurements, the sum of QRS duration + PR interval was the best predictor of mortality as shown by the area under the receiver operating characteristic curve of 85%, sensitivity of 70% and specificity of 84%. CONCLUSIONS: These findings suggest that silent cardiac dysfunction in DM1 patients may cause significant disturbances that over time result in serious complications. Regular follow-up of such patients with detailed electrical and mechanical cardiac assessment may suggest a need for early intervention that may avoid early mortality in some.

Ventricular dysfunction in type 1 myotonic dystrophy: electrical, mechanical, or both?

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a systemic disease which affects the heart and may be a cause of sudden death. Conduction disturbances are the major cardiac abnormalities seen in this condition. We sought to assess electrical and mechanical cardiac functions to identify abnormalities that might explain sudden cardiac death in DM1. METHODS: Thirty six patients with DM1 and 16 controls were studied using echocardiography including myocardial Doppler. ECG recordings were also obtained. RESULTS: Left ventricular (LV) dimensions were maintained but systolic function was reduced (p<0.001), including stroke volume (p<0.05). LV segmental myocardial isovolumic contraction time was prolonged (p<0.001) and correlated with PR interval (p<0.001). Isovolumic relaxation time was prolonged (p<0.05) and filling time was reduced (p<0.001). LV cavity was significantly asynchronous demonstrated by prolonged total isovolumic time (t-IVT) (p<0.001), high Tei index (p<0.001) and low ejection index (p<0.001). Right ventricular (RV) strain was reduced (p<0.001) as were its systolic and diastolic velocities (p<0.05 for both). 22/36 patients had prolonged LV t-IVT>12.3 s/min (upper 95% normal CI), 13 of whom had PR≥200 ms, 11 had QRS duration>120 ms (5 had combined abnormality) and the remaining 5 had neither. Over the 3 years follow up 10 patients had events, 6 of them cardiac. t-IVT was prolonged in 5/6 patients, PR interval in 4 and QRS duration in one. CONCLUSIONS: In DM1 patients, LV conventional measurements are modestly impaired but cardiac time relations suggest marked asynchronous cavity function. Although our findings were primarily explained on the basis of long PR interval or broad QRS duration a minority presented an evidence for myocardial cause of asynchrony rather than electrical. Early identification of such abnormalities may guide towards a need for additional electrical resynchronization therapy which may improve survival in a way similar to what has been shown in heart failure trials.

Pulsed tissue Doppler and strain imaging discloses early signs of infiltrative cardiac disease: a study on patients with familial amyloidotic polyneuropathy.

BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is a hereditary systemic amyloidosis with cardiac involvement. As early identification of the cardiac involvement is of major clinical interest we performed this study to test the hypothesis that tissue Doppler imaging (TDI) and strain imaging (SI) might disclose cardiac involvement in patients with early stages of FAP. METHODS: Twenty-two patients with FAP and 36 healthy controls were studied. Standard M-mode and Doppler echocardiography were performed. TDI and SI were used to assess the regional longitudinal left ventricular (LV) lateral and septal and right ventricular (RV) wall functions. All time intervals were corrected for heart rate by dividing with R-R interval and presented as percentage. RESULTS: We found that patients in comparison with controls had increased LV and RV wall thickness and by using TDI a prolonged isovolumic relaxation time (IVRt) at the septal segment (15.0+/-7.0 vs 10.7+/-4.1%, p<0.05) and prolonged isovolumic contraction time (IVCt) at LV lateral (12.8+/-4.3 vs 10.1+/-3.3%, p<0.05), septal (12.5+/-3.5 vs 8.9+/-1.9%, p<0.001) and RV free wall segments (12.0+/-3.6 vs 8.3+/-2.1%, p<0.001). Strain was reduced at LV lateral basal segment (-4.6+/-14.0 vs -20.2+9.1, p<0.001), RV free wall mid segment (-16.2+/-12.8 vs -29.4+/-15.2) as well as both septal segments (-4.1+/-11.7 vs -16.2+/-9.0%, p<0.001, -8.8+/-11.5 vs -19.4+/-8.4%, p<0.001 for septal basal and mid-segment). Even in the absence of septal hypertrophy the septal strain was reduced and the regional IVCt was prolonged. CONCLUSIONS: This is the first clinical study using TDI and strain in patients with FAP showing functional abnormalities before any morphological echocardiographic abnormalities were present. Both the left and right heart functions are involved and the disease should therefore be regarded as biventricular.

Autonomic cardiovascular regulation in patients with obstructive sleep apnoea: a study based on spectral analysis of heart rate variability.

The aim of this study was to assess the function of the autonomic nervous system in patients with obstructive sleep apnoea syndrome (OSAS). The study was designed as a cross-sectional case-control study. Fifty-one patients were included, and the findings were compared with those in 66 controls. Spectral analysis of heart rate variability (HRV) during supine rest, during controlled breathing and after tilting was performed in each patient and control case. The patients performed overnight sleep recordings the night before the HRV recordings. Individuals with an apnoea-hypopnoea index (AHI) above 20 were regarded as OSAS patients and those with AHI lower than 20 as snorers. Differences in HRV and blood pressure between patients and controls were analysed by multiple linear regression with age, body mass index and sex as independent variables. During free and controlled breathing there was a significant decrease in indices reflecting vagal modulation, indicating parasympathetic dysfunction in OSAS patients compared with controls. The mid-frequency component was also significantly reduced in OSAS patients after tilting but not in the lying position. This may be related to the parasympathetic dysfunction, but could also indicate a decreased sympathetic reserve capacity. We found no significant relation between AHI and indices of vagal modulation in the patient group. Our findings show an autonomic dysfunction in patients with OSAS. The dysfunction involves the parasympathetic system, and may be related to the increased cardiovascular mortality and malignant arrhythmia described in OSAS.

Adrenal steroid dysregulation in dystrophia myotonica.

OBJECTIVE: To evaluate circulating adrenal steroid hormones, cortisol diurnal rhythm and the negative feedback function of the cortisol axis in patients with dystrophia myotonica (DyM), a disease where metabolic disturbances, peripheral insulin insensitivity and cognitive dysfunction are common features. DESIGN: Morning serum levels of dehydroepiandrosterone sulphate, androstenedione, 17 alpha-hydroxy progesterone and cortisol; morning serum levels of testosterone and insulin; diurnal rhythm of saliva cortisol; and an overnight dexamethasone suppression test, together with a cognitive screening test in men with DyM and in controls. SETTING: Outpatient clinic in co-operation with Umeå University Hospital. SUBJECTS: Fifteen men with DyM and 13 age-matched controls. MAIN OUTCOME MEASURES: Adrenal steroid hormone levels, diurnal rhythm of saliva cortisol, dexamethasone suppression test and Mini Mental State Examination scores. RESULTS: Morning serum levels of dehydroepiandrosterone sulphate, androstenedione and 17 alpha-hydroxy progesterone were significantly decreased in DyM after inclusion of age and body mass index in multiple regression analyses (48, 26 and 32% decreases, respectively). An abnormal diurnal rhythm of saliva cortisol was present in all patients, mean saliva cortisol levels being significantly increased (33%) in DyM patients. Dexamethasone suppressibility did not differ between groups. DyM patients scored significantly lower on the Mini Mental State Examination (P < 0.001). CONCLUSIONS: These results indicate an abnormal adrenal steroid hormone secretion in DyM, which may contribute to peripheral insulin sensitivity as well as cognitive impairment in these patients.

Ischemic stroke. Impact of a recent myocardial infarction.

BACKGROUND AND PURPOSE: The risk of ischemic stroke is increased after a myocardial infarction. We quantified the stroke risk and evaluated ischemic stroke characteristics after an acute myocardial infarction. METHODS: A case-control study including patients with first-ever stroke was undertaken. Cases (n=103) were recorded prospectively in the population-based Northern Sweden World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study. Two controls per case with a stroke but without a recent myocardial infarction were matched for age, sex, and year of stroke onset. RESULTS: The sudden onset of neurological symptoms (76.7% versus 54.9%, P<0.001), impairment of consciousness (35.0% versus 18.4%, P<0.01), and a progression in neurological deficits (19.4% versus 8.7%, P<0.01) were more common in cases, while the onset of stroke during sleep was rarer in cases (6.8% versus 21.4%, P<0.01). In cases and controls, the clinical subclasses of stroke were as follows: total anterior circulation infarcts, 51.5% versus 37.9% (P<0.05); partial anterior circulation infarcts, 28.2% versus 26.7% (P=NS); lacunar infarcts, 4.8% versus 27.2% (P<0.001); and posterior circulation infarcts, 15.5% versus 8.2% (P=0.051). During the first 28 days after myocardial infarction, the daily rate of stroke declined rapidly from approximately 9 to 1 stroke per 10 000 myocardial infarction patients compared with an age-adjusted average daily stroke rate of 0.14 per 10 000 in the MONICA population. CONCLUSIONS: We conclude that the clinical characteristics of the stroke differ between patients with and without a recent myocardial infarction. The risk of a first-ever ischemic stroke is highest during the first few days after a myocardial infarction, but it then declines rapidly, and the absolute number of stroke events is low.

Spectral analysis of heart rate variability in patients with irritable bowel syndrome.

BACKGROUND: Autonomic dysfunction, both adrenergic and cholinergic, has been associated with the irritable bowel syndrome (IBS). The accuracy of the methods in use, however, has been limited by the need for active co-operation by the patients, with consequent difficulties in standardization. The aim of this study was to investigate the function of the autonomic nervous system in patients with IBS by using spectral analysis of the heart rate variability, an accurate method depending very little on patient cooperation. METHODS: Eighteen patients with IBS were compared with 36 sex- and age-matched controls. Spectral analysis of heart rate variability was performed to quantify sympathetic and parasympathetic nerve activity. RESULTS: The patients with IBS had significantly higher sympathetic activity than controls (P = 0.005). There was no significant (P = 0.308) increase in parasympathetic activity. There were no significant differences in heart rate or blood pressure between the patients and controls. CONCLUSION: Spectral analysis of heart rate variability has been used to assess the function of the autonomic nervous system in patients with IBS. IBS patients have significantly increased symphathetic activity, whereas parasympathetic activity does not differ from that of controls.

Impact of liver transplantation on autonomic neuropathy in familial amyloidotic polyneuropathy: an evaluation by spectral analysis of heart rate variability.

OBJECTIVES: To evaluate the impact of liver transplantation on familial amyloidotic polyneuropathy type I (FAP) patients' autonomic neuropathy. DESIGN: An open study. SETTING: A tertiary referral centre. SUBJECTS: Twelve liver-transplanted FAP patients evaluated before and one year or longer after liver transplantation. INTERVENTIONS: Spectral analysis of heart rate variability. The low-frequency band after tilting (sympathetic), and the high-frequency band in supine position (parasympathetic) were analysed, as were the pulse and blood pressure reaction to tilting. Clinical symptoms related to autonomic disturbances were recorded. MAIN OUTCOME MEASURES: Spectral band power for sympathetic and parasympathetic activity. RESULTS: No statistically significant improvements in sympathetic or parasympathetic band power after liver transplantation was found (sympathetic band power: 2.7 (2.2-3.2) before, 2.9 (2.2-3.6) after; parasympathetic 2.0 (1.6-2.4) before and 2.0 (1.7-2.3) after. A significant correlation was noted between orthostatic blood pressure reaction and sympathetic activity before transplantation, but not after the operation. A trend was noted for improved orthostatic blood pressure reaction. Symptomatic improvements in bowel function and orthostatic symptoms were reported by several patients. CONCLUSIONS: Although improvements in autonomic symptoms are reported after liver transplantation, no significant improvement is noted in sympathetic or parasympathetic spectral band power of heart rate variability. However, the follow-up period of 17 months may be too short. Further evaluation after an additional two and four years is needed.

Impact of autonomic neuropathy on circulatory instability during liver transplantation for familial amyloidotic polyneuropathy.

BACKGROUND: Circulatory instability with severe hypotension frequently complicates liver transplantation in patients with familial amyloidotic polyneuropathy. Autonomic dysfunction is found early in the course of the disease by analysis of beat-to-beat heart rate variability (HRV). The aim of the present study was to investigate the impact of autonomic neuropathy on intraoperative circulatory instability during liver transplantation for familial amyloidotic polyneuropathy. METHODS: Twenty-two patients were evaluated at the Department of Medicine, Umea University Hospital, by spectral analysis of HRV and later received liver transplants at Huddinge University Hospital. The low-and high-frequency bands obtained by spectral analysis of HRV in the supine and upright positions, respectively, were used as representative of sympathetic and parasympathetic activity. Circulatory instability during transplantation was defined as a fall in systolic arterial blood pressure below 70 mmHg for more than 5 min during the preanhepatic phase. RESULTS: Both arrhythmia preventing spectral analysis of HRV and a sympathetic variability peak below 2.5 mHz2 were significantly more common among patients with intraoperative circulatory instability (P=0.03 and 0. 004, respectively). A diminished increase in pulse rate when tilting the patients from the supine to the upright position was also more pronounced among patients with circulatory instability (P<0.05). CONCLUSIONS: The majority of patients who will develop circulatory instability with a pronounced fall in arterial blood pressure can be identified by Poincare plots of R-R intervals and spectral analysis of HRV. A low sympathetic peak or arrhythmia precluding spectral analysis of HRV is significantly related to operative circulatory instability.

Assessment of autonomic nerve function in acute intermittent porphyria; a study based on spectral analysis of heart rate variability.

OBJECTIVES: To assess the function of the autonomic nervous system in patients with acute intermittent porphyria by spectral analysis of the heart rate variability. DESIGN: A cross-sectional case-control study. SETTING: Patients were examined at the Primary Health Care Centre, Arjeplog and at Umeå University Hospital, where the controls were also examined. SUBJECTS: Twenty-three patients with acute intermittent porphyria verified by DNA analysis and 92 healthy controls were included. MAIN OUTCOME MEASURES: The mid-frequency band power after tilting was used to evaluate sympathetic function, and the high frequency band power during controlled breathing at 12 breaths min-1 and the mid-frequency band power during controlled deep breathing at 6 breaths min-1 were used to evaluate parasympathetic function. RESULTS: There was no evidence of sympathetic dysfunction in the patients. The mid-frequency band power during controlled deep breathing at 6 breaths min-1 was significantly (P = 0.02) lower in the patient group. CONCLUSIONS: Our findings indicate a parasympathetic dysfunction in patients with acute intermittent porphyria. This may be causally related to sudden cardiac death and the life-threatening arrhythmias which have been observed in this disorder.

Predictive value of tissue plasminogen activator mass concentration on long-term mortality in patients with coronary artery disease. A 7-year follow-up.

BACKGROUND: The fibrinolytic system is part of the defense against thrombotic and cardiovascular events, but so far no study has shown that clinical measurements of fibrinolytic key components such as tissue plasminogen activator (t-PA) or plasminogen activator inhibitor type 1 (PAI-1) have any predictive value beyond 3 years. METHODS AND RESULTS: In 1983 through 1985, 213 consecutive patients with angina pectoris and angiographically verified coronary artery disease were sampled, and the mass concentration of t-PA and the activity of PAI-1 were measured in citrated plasma samples. At a mean follow-up time of 7 years, the all-cause mortality was checked. No patient was lost to follow-up. The data were analyzed by Cox regression, and t-PA mass concentration was found to be the only laboratory risk factor significantly related to mortality in all patients (P < .022) and also in the major subgroup (78% of all patients) subjected to coronary bypass surgery (P < .027). In the latter subgroup, body mass index was also related to mortality. CONCLUSIONS: An increased mass concentration of t-PA is a new risk factor of long-term mortality in patients with angina pectoris and coronary artery stenosis. This paradoxical effect probably reflects increased t-PA levels attributable to enzyme inhibitor complex formation in subjects with increased plasma levels of t-PA inhibitors.

Heart-rate variation: what are we measuring?

Many methods have been proposed during the last two decades for the assessment of autonomic nervous system function by quantification of the heart-rate variation (HRV). Relatively little has been written about the HRV in relation to physiological models of the heart-rate regulation. The integral pulse frequency model (IPFM) is a simple model that describes the genesis of heartbeats under the influence of the autonomic nervous system. By comparing simulated HRV data generated with the IPFM model with data from healthy volunteers we found similarities indicating that the model accurately reflects real data. Furthermore, we found a considerable difference between HRV measurements based on beat-by-beat heart-rate and measurements based on the heartbeat interval. Our results suggest that the commonly used electrocardiographic RR interval representation of heart-rate variation might possess an inherent nonlinear, mean heart-rate-dependent property indicating that analysis directly based on RR intervals can give biased results with respect to the underlying autonomic activity. The conclusions embrace all measurements of variation that are directly based on RR intervals including simple indices as well as higher-level quantification such as spectral analysis.

Tissue plasminogen activator and other risk factors as predictors of cardiovascular events in patients with severe angina pectoris.

The value of measurements of the fibrinolytic factors, tissue plasminogen activator and plasminogen activator inhibitor, for predicting death and non-fatal cardiovascular events was studied in 213 consecutive patients with angiographically documented coronary artery disease. In the course of 4-year follow-up, 47 patients (22.1%) had at least one cardiovascular event. We found the incidence of cardiovascular events to be positively associated with high tissue plasminogen activator antigen concentration, in addition to previous myocardial infarction, low ejection fraction, hypertension, high body mass index and high triglyceride levels. Cholesterol was not found to be associated with cardiovascular events. A high concentration of tissue plasminogen activator antigen thus implies an increased risk of cardiovascular events in patients with severe angina pectoris.

Assessment of hypothalamic-pituitary function in patients with familial amyloidotic polyneuropathy.

This study was performed to evaluate hypothalamic-pituitary hormone regulation in patients with familial amyloidotic polyneuropathy. Twenty-two patients without clinically overt endocrinological dysfunction were studied. A thyrotropin-releasing hormone test revealed abnormal growth hormone regulation in 9 of 17 (53%) patients, and abnormal prolactin regulation in 9 of 18 (50%) patients. Abnormalities in either growth hormone or prolactin regulation were found in 12 of 17 (71%) patients. Serum somatomedin C levels were normal in all 22 patients. In 3 of 18 (17%) patients the plasma arginine vasopressin levels were low relative to the serum osmolality levels. Thus abnormalities in hypothalamic-pituitary hormone regulation may be common in familial amyloidotic polyneuropathy.

Assessment of autonomic nerve function in myotonic dystrophy.

The function of the autonomic nervous system was studied in 23 patients with myotonic dystrophy, from a defined population in northern Sweden with an extremely high prevalence of this disease. Heart rate variability tests showed only minor signs of parasympathetic dysfunction. Blood pressure and plasma noradrenaline measurements in recumbent and upright positions showed no signs of sympathetic neuropathy. Increased plasma levels of noradrenaline was an unexpected finding. Our study does not support the hypothesis that cardiac arrhythmias, orthostatic hypotension, gastrointestinal motility disturbances and urinary bladder dysfunction in myotonic dystrophy are caused by autonomic neuropathy, and we believe that these symptoms should rather be ascribed to a defective function of the target organs.

Cardiac involvement in congenital myotonic dystrophy.

Seven young patients (mean age 19 years 8 months) with congenital myotonic dystrophy and with defined symptoms at birth were investigated by electrocardiography and echocardiography. None had cardiovascular symptoms. Electrocardiograms or echocardiograms or both were abnormal in all patients. Atrioventricular and intraventricular conduction defects were the most common electrocardiographic abnormalities and were seen in five patients. The echocardiographic examinations showed impaired left ventricular systolic function in one patient. Other echocardiographic findings were a small left ventricle and atrium, minor valve defects, and mitral valve prolapse. This study shows that the heart is often affected in young patients with congenital myotonic dystrophy. The specialised conduction system is often affected and so too is the myocardium, causing impaired systolic function.

Reduced levels of tissue plasminogen activator and plasminogen activator inhibitor in plasma of patients with familial amyloidotic polyneuropathy.

Tissue plasminogen activator (tPA) antigen levels and plasminogen activator inhibitor (PAI) activity were measured in the plasma from 23 patients with familial amyloidotic polyneuropathy. Both tPA levels and PAI activity were reduced to about half normal, even when the effects of patient age and body mass index were taken into account. There were higher mean tPA levels and PAI activity in patients with mild disability than in those with moderate or severe disability, but these differences were not statistically significant. There were normal tPA levels after venous occlusion of the upper arm, indicating a normal capacity of vascular endothelium to release tPA. This is the first reported disorder with reduced rather than increased basal tPA and PAI levels. The pathogenetic and clinical significances of these disturbances so far remain obscure.

Assessment of thyroid and adrenal function in patients with familial amyloidotic polyneuropathy.

This study was performed to evaluate thyroid and adrenal function in patients with familial amyloidotic polyneuropathy. Twenty-four patients without any clinical overt endocrinological dysfunction were studied. None of the patients showed laboratory evidences of hypo- or hyperthyroidism. A short ACTH-stimulation test was performed in 17 of the patients. A low cortisol response to ACTH stimulation, suggesting adrenocortical insufficiency, was found in four (24%) of the patients, and an intermediate response interpreted as suspected hypofunction was found in three (18%) patients. Low serum dehydroepiandrosterone sulphate levels, suggesting adrenal hypofunction, were found in six (25%) of the patients. We believe that the possibility of glucocorticoid insufficiency should always be considered in patients with familial amyloidotic polyneuropathy.

Autonomic neuropathy in familial amyloidotic polyneuropathy. A clinical study based on heart rate variability.

Familial amyloidotic polyneuropathy (FAP) is characterized by both sensimotor and autonomic dysfunction. Autonomic disturbance involving the gastrointestinal tract, the urinary bladder, the cardiac conduction system, and the peripheral circulation has been described. In this study simple, non-invasive tests of autonomic function based on heart rate variability were applied to 12 patients with FAP and 12 healthy volunteers. The heart rate variation during normal breathing, deep breathing and during tilt from recumbent to standing position was measured. All tests showed significantly less heart rate variation in patients than in controls and the heart rate variation decreased with increasing severity of neurological disability, but the small number of patients in our study does not allow any further comparison between subgroups. Our study thus indicates impaired cardiovascular autonomic function in patients with FAP and we believe that these findings might also be of importance in other forms of systemic amyloidosis.