Widespread electroanatomic alterations of right cardiac chambers in patients with myotonic dystrophy type 1

INTRODUCTION: Conduction disturbances and arrhythmias characterize the cardiac feature of myotonic dystrophy type 1 (MD1); a myocardial involvement has been suggested as part of the cardiac disease. The aim of our study was to investigate the underlying myocardial alterations using electroanatomic mapping (CARTO) and their possible correlation with genetic and neurological findings. METHODS AND RESULTS: Right atrial and ventricular CARTO maps were obtained in 13 MD1 patients. Thirteen age-matched patients with paroxysmal supraventricular tachycardia and normal heart served as controls. Unipolar voltage (UNI-v), bipolar voltage (BI-v) amplitudes, bipolar potential duration (Bi-dur), and atrial propagation time (A-pt) were measured. UNI-v and BI-v in interatrial septum, anterolateral atrial wall, and right ventricle outflow tract were lower in MD1 patients than controls (P < 0.001). Bi-dur and A-pt were longer in MD1 patients than controls (P < 0.001, P = 0.046, respectively). A significant relationship was documented between CTG triplets and the percentage of Bi-v <0.5 mV in the atrial anteroseptal region (r = 0.6, P = 0.02). CONCLUSIONS: Altered electroanatomic patterns are present in the right cardiac chambers in MD1 patients. Widespread myocardial alterations, not necessarily limited to the conduction system, may support the presence of a cardiac myopathy as part of the disease.     

Functional abnormalities of the anal sphincters in patients with myotonic dystrophy

Motility of the anorectal area was studied in 19 patients with myotonic dystrophy and in 20 control subjects, before and after pudendal block. In patients with myotonic dystrophy, before anesthesia, resting pressure in the upper anal canal ( p less than 0.001) and duration and amplitude of relaxation of the rectoanal inhibitory reflex (p less than 0.01) were decreased. A myotonic contraction of high amplitude followed relaxation in all patients, but in control subjects this was not the case. In the lower anal canal, the duration of the rectoanal contractile reflex was prolonged as compared with control subjects (p less than 0.001). The pudendal block had no effect in the upper anal canal either on resting pressure or on amplitude and duration of the rectoanal inhibitory reflex, neither in patients nor in controls. After blockade, however, the myotonic contraction subsequent to the reflex in patients was significantly reduced in amplitude (p less than 0.01). In lower anal canal, the resting pressure was reduced to similar levels, both in patients and in control subjects, after pudendal block (p less than 0.01), and the rectoanal contractile reflex was abolished in both groups. This study demonstrates a number of functional abnormalities in the anorectal structures of patients with myotonic dystrophy. These abnormalities produce a decrease in resting pressure in the anal canal, and a reflex myotonic contraction subsequent to rectal distention due to both external and internal sphincter dysfunction.     

High prevalence of cardiac involvement in patients with myotonic dystrophy type 1: A cross-sectional study

Background

Patients with myotonic dystrophy type 1 (DM1) have a three-fold higher risk of sudden cardiac death (SCD) than age-matched healthy controls. Despite numerous attempts to define the cardiac phenotype and natural history, existing literature suffers from low power, selection-bias and lack of controls. Thus, the optimal strategy for assessing cardiac involvement in DM1 is unclear.

Method

In this large single-centre study, we evaluated 129 unselected DM1 patients (49.6% men), mean (SD) age 44 (14.7) years with family history, physical examination, electrocardiogram (ECG), echocardiography, Holter-monitoring and muscle strength testing.

Results

Cardiac involvement was found in 71 patients (55%) and included: 1) Conduction abnormalities: atrio-ventricular block grade I (AVB grade I) (23.6%), AVB grade II (5.6%), right/left bundle branch block (5.5/3.2%) and prolonged QTc (7.2%); 2) arrhythmias: atrial fibrillation/flutter (4.1%), other supraventricular tachyarrhythmia (7.3%) and non-sustained ventricular tachycardia (4.1%); and 3) structural abnormalities: left ventricular systolic dysfunction (20.6%) and reduced global longitudinal strain (21.7%). A normal ECG was not significantly associated with normal findings on Holter-monitoring or echocardiography. Patients with abnormal cardiac findings had weaker muscle strength than those with normal cardiac findings: ankle dorsal flexion (median (range) 4.5 (0–5) vs. 5.0 (2.5–5), p = 0.004) and handgrip (median 4.0 (0–5) vs. 4.50 (2–5), p = 0.02).

Conclusion

The cardiac phenotype of DM1 includes a high prevalence of conduction disorders, arrhythmias and risk factors of SCD. Systematic cardiac screening with ECG, Holter-monitoring and echocardiography is needed in order to make a proper characterization of cardiac involvement in DM1.     

Hyperproinsulinaemia in patients with myotonic dystrophy

Summary Hyperinsulinaemia is a reported feature of the inherited multisystem disorder myotonic dystrophy. This phenomenon has been attributed to a compensatory beta cell response to tissue insulin resistance. In this study, circulating concentrations of insulin, proinsulin, and split proinsulin molecules were determined after an overnight fast in ten patients with myotonic dystrophy using two-site monoclonal antibody-based immunoradiometric assays. Results were compared with ten healthy control subjects matched for age, gender, and body mass index. Oral glucose tolerance (75 g), as defined by World Health Organization criteria, was normal in all subjects. Fasting plasma immunoreactive insulin concentration, as determined using a conventional radioimmunoassay, was almost three times higher (p<0.005) in the myotonic dystrophy patients than the healthy control subjects. By contrast, fasting concentrations (mean±SEM) of C-peptide (0.75±0.09 vs 0.52±0.03 nmol/l, p=0.07) and immunoradiometrically-determined insulin (60±12 vs 38±4 pmol/l, p=0.09) were not significantly different between the groups. Fasting concentrations of proinsulin (10.3±2.9 vs 1.6±0.3 pmol/l, p<0.01), and 32–33 split proinsulin (7.8±2.5 vs 2.9±0.4 pmol/l, p<0.05) were significantly elevated in the patients with myotonic dystrophy. Accordingly, the mean fasting proinsulininsulin ratio, expressed as a percentage, was significantly increased in the myotonic patients (20±5 vs 4±1%, p<0.01). The overall C-peptide response to the oral glucose challenge was significantly greater in the myotonic patients compared with the healthy control subjects (p<0.001). These results provide corroborative evidence of increased beta-cell secretion in myotonic dystrophy. In addition, myotonic dystrophy is characterised by elevated plasma concentrations of proinsulin-like molecules which may cross-react in insulin radioimmunoassays.     

Hyperparathyroidism in patients with myotonic dystrophy

This study was designed to determine the possible presence of abnormal calcium metabolism in patients with myotonic dystrophy (MyD). Twenty-five patients with MyD, 13 patients with other neuromuscular disorders (non-MyD), and 12 normal subjects were studied. The mean plasma 1,25-dihydroxyvitamin D level in the MyD patients [83.2 +/- 23.1 (+/- SD) pmol/L] was significantly higher than those in the other two groups [normal subjects, 49.7 +/- 15.4 (P less than 0.01); non-MyD patients, 51.6 +/- 27.4 (P less than 0.01)]. On the contrary, the mean plasma 24,25-dihydroxyvitamin D levels were similar in the MyD patients and the normal subjects. The increments in serum calcium levels and urinary calcium excretion after oral calcium loading in the MyD patients were significantly greater than those in the normal subjects, suggesting that intestinal calcium absorption was augmented in the MyD patients. The mean nephrogenous cAMP excretion in the MyD patients (1.71 +/- 1.08 nmol/100 mL glomerular filtrate) also was higher than those in the other two groups (0.93 +/- 0.34 in the non-MyD patients; 0.91 +/- 0.21 in normal subjects). These results suggest that parathyroid function may be increased in MyD patients.     

Profound cardiac conduction delay predicts mortality in myotonic dystrophy type 1

Abstract. Mörner S, Lindqvist P, Mellberg C, Olofsson B‐O, Backman C, Henein M, Lundblad D, Forsberg H (Umeå University Hospital, Umeå; Umeå University, Umeå; Sunderby Hospital, Luleå; Sweden). Profound cardiac conduction delay predicts mortality in myotonic dystrophy type 1. J Intern Med 2010; 268 :59–65. 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.     

Microvascular ischemia in patients with myotonic dystrophy

Two women with myotonic dystrophy underwent dipyridamole thallium-201 (201Tl) myocardial perfusion imaging, after which one patient developed flat T waves in lead I and aV(L), and inverted T waves in leads V(2-6). The other patient developed a nonspecific intraventricular block that progressed to complete left bundle branch block and was associated with chest discomfort. Reversible scintigraphic defects were observed in both women. Although there was evidence that suggested myocardial ischemia on the ECG changes and 201Tl scintigraphic findings, coronary angiography demonstrated no significant stenoses in either patient. These findings suggest that microvascular dysfunction may lead to myocardial ischemia and conduction disturbances in patients with myotonic dystrophy.     

Unusual cardiac manifestations in a patient with myotonic muscular dystrophy

We report on a patient with myotonic muscular dystrophy in whom mitral valve prolapse associated with prolonged PR interval and left anterior hemiblock was documented 3 years before any clinical evidence of myotonia, muscle weakness or wasting. One year after diagnosis had been established, he developed atrial flutter with 1:1 atrioventricular conduction, an arrhythmia that in addition to complete heart block and ventricular arrhythmias may account for the occurrence of syncope and sudden death in this group of patients.     

Hypothalamic-pituitary-testicular function in 70 patients with myotonic dystrophy

Hypothalamic-pituitary-testicular function was studied in 70 patients with myotonic dystrophy (MD). The diagnosis was confirmed by electromyography. The mean age of the patients was 36.2 +/- 13.2 yr and the duration of the disease was 11.17 +/- 8.01 yr. Testicular atrophy (testes less than or equal to 12 ml on a Prader orchidometer) was present in 65.5% of patients. Fertility among married patients was 66.6%. Mean testosterone plasma levels were 438 +/- 298 ng/dl vs 520 +/- 185 ng/dl in the control group (P = NS). Basal plasma FSH and LH levels, and their response after the administration of 100 mcg of LH-RH were significantly increased although a wide dispersion was observed. Sperm count was carried out in 27 cases, showing a normal count in 7, oligospermia in 12, and azoospermia in 8 patients. Testicular biopsy was performed in 45 patients being normal in 2, showing mild testicular damage in 8, moderate in 14, and severe in 18; it was nule in 3 of them. A significant relationship between testicular atrophy and the sperm count (p less than 0.01), testicular damage and testicular atrophy (p less than 0.025), and sperm count and testicular damage (p = 0.017) was found. Basal plasma FSH and LH level were significantly related to the degree of damage in the testicular biopsy. All these findings indicate a primary testicular pathology, prevailing tubular over interstitial damage. We have not found any association between the duration of the disease and gonadal dysfunction.     

Prevalence of cardiac structural and functional abnormalities in untreated primary hypertension

We examined the prevalence of left ventricular structural and functional abnormalities in previously untreated subjects by performing echocardiography in 89 normal volunteers, 57 patients with established hypertension, and 38 patients with mild or borderline hypertension. We measured left ventricular mass, wall thickness, internal diameter, and wall thickness/radius ratio. Because of intergroup differences in body size, we used covariance analysis to index these variables to a common value of 1.8 m2. No adjustment was needed for the wall thickness/radius ratio. Functional variables determined were fractional shortening and transmitral early/late flow velocity ratio (the latter was standardized by analysis of covariance to age 40 years). The prevalence of left ventricular mass index values more than 2 SD above the mean of the normal group was 30% in the patients with established hypertension and 12-15% in the patients with mild hypertension. Corresponding figures for wall thickness index were 65% and 32% and for the wall thickness/radius ratio 60% and 40%. The prevalence of abnormality in the transmitral flow velocity was 28% in the patients with established hypertension and 12% in the patients with mild hypertension. A multivariate discriminant function that used combined anatomic and functional variables provided the most reliable classification; it was correct in 82% of normal subjects, 65% of patients with established hypertension, and 61% of patients with mild hypertension. The majority of patients with hypertension have cardiac structural or functional abnormalities, or both.     

Hypothalamic-pituitary-gonadal function in patients with myotonic dystrophy.

Gonadal function was studied in three post-pubertal siblings (two male and one female) and one unrelated male patient with myotonic dystrophy. The diagnosis was confirmed in all cases by electromyography and muscle biopsy. Basal levels of plasma immunoreactive LH, FSH, testosterone, and estradiol were measured. Hypothalamic, pituitary, and gonadal reserve and responsiveness were evaluated by clomiphene, LHRH, and HCG tests. Histologic examination of gonadal biopsies was also performed. The results showed that gonadal failure present in the four patients had different characteristics. In the same family, hypothalamic amenorrhea was observed in the female patient, and hypothalamic eunuchoidism and hypergonadotropic hypogonadism with marked tubular and leydig cells failure in the male patients. The non-related male patient had hypergonadotropic hypogonadism with tubular failure but with a compensatory leydig-cell hyperplasia. These data are interpreted as demonstrating different expressivity of the hypogonadism associated with the same inherited muscle disease.     

Impaired vasopressin secretion in patients with myotonic dystrophy

Hypernatremia has occasionally been observed in patients with myotonic muscular dystrophy (MyD). To elucidate the possibility of osmoregulatory dysfunction, we investigated hypothalamo-posterior pituitary function as well as serum electrolytes in eight patients with MyD. Blood samples were obtained early in the morning after overnight dehydration. Renal function was estimated by blood urea nitrogen, serum creatinine and creatinine clearance. Posterior pituitary function was evaluated by direct measurement of plasma vasopressin (AVP) during a 5% hypertonic saline infusion. Plasma AVP concentrations were determined by sensitive radioimmunoassay. In five patients, circulating blood volume (CBV), plasma renin activity (PRA) and serum aldosterone (S-Aldo.) were also measured. The mean serum sodium level (143.9 +/- 1.7mEq/1: Mean +/- SD) was significantly higher than in the controls (139.4 +/- 2.2mEq/1). A 5% hypertonic saline infusion showed a subnormal increase in AVP and diminished thirst, despite sufficient elevation of plasma osmolality, in all patients as compared with healthy adults. Renal function was intact. Biochemical evidence of dehydration, estimated by PRA, S-Aldo and CBV, was unremarkable in four of the five patients. These findings suggest that patients with MyD have neurogenic disorders of osmoregulation in addition to previously reported endocrine abnormalities. Impaired AVP secretion in response to osmotic stimuli and reduced thirst might be responsible for such failure.