Home infusion program with enzyme replacement therapy for Fabry disease: The experience of a large Italian collaborative group.

Fabry disease (FD) [OMIM 301500] is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive multisystem accumulation of globotriaosylceramide (Gb3). Although the introduction of Enzyme Replacement Therapy (ERT) resulted in a variety of clinical benefits, life-long intravenous (IV) treatment with ERT with an every other week schedule, may interfere with daily life activities and impact on QoL. We report here a multicentric, observational, longitudinal data analysis on a large cohort of 85 Italian FD patients (45 males, 40 females) from 11 out of 20 Italian regions, who received a cumulative number of 4269 home infusions of agalsidase alfa. For the whole cohort, the average duration of home therapy was 1 year and 11 months (range 3 months-4 years and 6 months), and during this period, compliance to treatment (number of infusions performed vs scheduled) reached 100%. The EQ-5 VAS scale was administered to patients to evaluate the self-reported QoL, 58% of patients showing an increase of EQ-5 VAS score at follow up compared to baseline (home treatment start) or remaining stable. A mild increase of average disease severity, measured through Mainz Severity Score Index (MSSI), was found during hospital treatment (p < 0,007), while it remained stable between the first home therapy infusion and last follow up. Interestingly, 4 out of 7 (57%) patients, showing an improvement in FD-related clinical status after starting home therapy, had previously a sub-optimal compliance to treatment during the period of hospital treatment management. Only 4 adverse non serious reactions (0,093%) were reported totally in 2 patients during home treatment. We conclude that home infusions in eligible patients with FD are safe, contribute to improve treatment compliance and therapeutic clinical outcomes, and may have a positive impact on self-perceived QoL.

Restrictive cardiomyopathy due to desmin accumulation in a family with evidence of autosomal dominant inheritance.

OBJECTIVE: A familial case of restrictive cardiomyopathy due to desmin accumulation characterized by severe disturbances of cardiac conduction is described. BACKGROUND: Desmin is an intermediate filament normally present in the myocardium, particularly in the Purkinje fibres, in the skeletal and in the smooth muscle. METHODS: Resting electrocardiogram, 2-dimensional and Doppler echocardiogram, cardiac catheterization, electrophysiological study have been performed in all siblings. Informed consent for endomyocardial biopsy was obtained only in one patient. RESULTS: The mother showed bilateral pes cavus and complained of episodes of vertigo at the age of 36 years. At that time she was submitted to electrophysiological study and to permanent pacing. After 15 years of good health conditions, she developed heart failure and underwent cardiac transplantation. A 21 year old son had a syncope; his ECG was similar to that of his mother; a permanent pacemaker was implanted and a diagnosis of restrictive cardiomyopathy with desmin accumulation was confirmed at histopathology study. Afterwards, another 24 year old sib had a syncope with head trauma: ECG showed right atrial enlargement, left bundle branch block. After electrophysiological study, he started antiarrhythmic therapy. This patient showed bilateral pes cavus. CONCLUSIONS: The early manifestation of desmin accumulation may be intraventricular conduction disorders that can be often controlled by pacemaker implantation. Clinical symptoms of heart failure may be absent for a long period of time. Pedigree analysis is most consistent of autosomal dominant inheritance.

Maternally inherited cardiomyopathy: a new phenotype associated with the A to G AT nt.3243 of mitochondrial DNA (MELAS mutation).

The A to G transition at nt.3243 of the tRNALeu(UUR) gene of mtDNA, commonly associated with MELAS, was detected in several members of a family affected by a maternally inherited form of hypertrophic cardiomyopathy. These findings suggest adding cardiomyopathy in the list of phenotypes associated with the 3243 mutation.

[Three-dimensional transesophageal echocardiography: a new cardiologic diagnostic tool. Initial experience with 150 patients]. / Ecocardiografia tridimensionale transesofagea: una nuova presenza nella diagnostica cardiologica. Esperienza iniziale su 150 pazienti.

BACKGROUND: Three-dimensional transesophageal echocardiography is a new diagnostic tool and its potential has been investigated mainly in international centers dealing with research in the field of cardiac pathologies. The clinical usefulness and the potential additional information over multiplane transesophageal echocardiography in daily clinical practice have not been exstensively studied. OBJECTIVES: This study sought to assess the feasibility and to define the potential role of three-dimensional technique in a clinical cardiology department. POPULATION AND METHODS: One hundred-fifty patients (73 males, 77 females) aged 17-82 underwent a three-dimensional transesophageal echocardiographic study. Indications for the study were the following: 39 mitral (26%), 13 aortic (8%) and 4 tricuspidal (2%) valvulopathies, 23 valvular prostheses (15%), 6 aortic diseases (4%), 16 sources of embolism (10%), 16 congenital heart diseases (10%), 14 ischemic heart diseases (9.3%), 14 cardiomyopathies (9%), 5 other pathologies (3%). The 3 D examination quality was graded as insufficient, sufficient and good. The information obtained by "volume rendered" and "anyplane" three-dimensional echocardiography were compared with the traditional two-dimensional images to determine whether they provided additional information. RESULTS: A total of 288 acquisitions were obtained in the 150 patients (1.9 acquisitions per patient). Examinations were graded of good quality in 99 patients (61%), sufficient in 36 (24%) and insufficient in 15 patients (10%). Additional informations were obtained in 33 patients (22%) by "volume rendered" echocardiography and by "anyplane echocardiography", including mitral regurgitation or repair for valvular prolapse (11 patients), aortic valve malformations and endocarditis (4 patients), congenital heart diseases (9 patients), right ventricular dysplasia (6 patients) or hypertrophic cardiomyopathy (1 patient), tricuspid regurgitation (2 patients). The additional information were obtained in patients in the group of good 3 D reconstructions quality in all but two cases. CONCLUSIONS: The diagnostic use of the transesophageal technique with 3 D facilities permitted to obtain an overall 22% of additional information. These results will stimulate further study to evaluate the advantages of the three-dimensional technique in specific clinical fields of application.

Evidence from family studies for autoimmunity in dilated cardiomyopathy.

Organ-specific antibodies are found in patients with autoimmune disease and their symptom-free relatives many years before clinical onset. Organ-specific cardiac antibodies can be found in patients with dilated cardiomyopathy (DCM) and their relatives, which supports the idea that DCM is an autoimmune disease. We did non-invasive cardiological assessment and antibody screening in 342 symptom-free relatives (170 male, 172 female, mean [SD] age 31 [16] years). 177 relatives were from 33 families with more than 1 affected individual (familial DCM) and 165 relatives from 31 families with only 1 affected member (non-familial DCM). The frequency of cardiac antibodies was higher among relatives of DCM patients than in controls (20% vs 3.5%, p = 0.0001). In 37 (58%) of the families studied, cardiac antibodies were found in the proband and/or in at least 1 family member and were more common in familial than in non-familial DCM (24% vs 15%, p = 0.036). Antibody-positive relatives were younger (26 [15] vs 33 [17] years, p = 0.01) and had a larger mean echocardiographic left ventricular end-systolic dimension (35 [6] vs 32 [6], p = 0.01 mm) and reduced percentage fractional shortening compared with antibody-negative relatives (31 [6] vs 34 [6], p = 0.008). Presence of cardiac-specific autoantibodies in symptom-free DCM relatives provides evidence of autoimmunity in a subset of our patients (58%), including familial and non-familial forms of DCM. These antibodies are associated with mild left ventricular systolic dysfunction on echocardiography and may be early markers for relatives at risk of DCM.

[Contractility and left ventricular filling in heart failure: an echocardiographic evaluation]. / La contrattilità e il riempimento del ventricolo sinistro nell'insufficienza cardiaca: valutazione ecocardiografica.

In this paper we analyze the possibility of investigating the various modalities of pump function alteration by the echocardiographic technique through examination of the different parts of the cardiac cycle. While M-Mode and 2D echocardiography make a precise assessment of the systolic function parameters possible, with the Echo-Doppler technique we can study diastolic function and obtain information about many hemodynamic parameters. "Strain dependent" and "strain independent" diastolic function are studied almost exclusively with the Echo-Doppler technique: the diagnosis of restrictive cardiomyopathy can be established without invasive procedures such as cardiac catheterization. We suggest that, in most heart diseases with cardiac failure, diastolic and systolic dysfunction coexist: in mitral and aortic regurgitation, echocardiography can give precise information on the presence of ventricular dysfunction, even in the presence of very few or no symptoms, which helps the cardiologist make an early surgical or non surgical decision when dealing with such valve pathologies.

Familial aggregation of idiopathic dilated cardiomyopathy: clinical features and pedigree analysis in 14 families.

OBJECTIVE: A recent prospective study in patients with dilated cardiomyopathy has reported that the disease is familial in at least 20% of cases, but the pattern of inheritance could not be ascertained. The presence of an autosomal dominant pattern, such as seen in hypertrophic cardiomyopathy, could make it possible to search for single gene defects with linkage analysis, whereas polygenic inheritance would be consistent with the autoimmune hypothesis. To assess the pattern of inheritance, we retrospectively identified patients with familial disease and assessed their first degree relatives (parents, siblings and children) for dilated cardiomyopathy. DESIGN AND PATIENTS: The family history of 105 consecutive patients with dilated cardiomyopathy was reviewed and 14 who had at least one first degree relative with documented disease were identified as probands. Their healthy relatives (109) were studied by physical examination, electrocardiography, M mode and cross sectional echocardiography, and were classified as unequivocally normal or as potential carriers. The potential carriers had abnormal electrocardiography with either at least one echocardiographic measurement of left ventricular cavity dimension or percentage fractional shortening outside 2 SDs of normal values (based on age and body surface area). The potential carriers underwent 24 hour Holter monitoring and maximal treadmill exercise. RESULTS AND CONCLUSION: Twenty three relatives (21%) were classified as potential carriers: 12 had an increased left ventricular end diastolic dimension, with reduced percentage fractional shortening in three; 11 had an abnormal electrocardiogram and increased end diastolic dimension, with reduced percentage fractional shortening in five. Such abnormalities were very mild and follow up is necessary to find whether such changes represent early disease. Pedigree analysis was most consistent with polygenic inheritance.

[Anatomo-functional study of non-rheumatic mitral insufficiency with transesophageal echocardiography]. / Studio anatomo-funzionale dell'insufficienza mitralica non reumatica con ecocardiografia transesofagea.

Reconstruction surgery of the mitral valve has become an alternative to mitral replacement in patients with pure mitral regurgitation. Preoperative assessment of the anatomic and functional aspects of the valvular lesion is of the utmost importance in conservative surgery. Transesophageal echocardiography is a new approach to investigating the mitral valve, and our study was undertaken with the purpose of determining its importance in the exploration of mitral regurgitation of non-rheumatic origin. Subjects included were twenty patients with pure and isolated mitral regurgitation (MR): 14 males and 6 females with an average age of 47 +/- 13 years. All the patients underwent a first transesophageal 2D and color Doppler echocardiographic examination, and 5 of them underwent a second one during cardiovascular surgery. Mitral anulus diameter, mitral valve cordae tendinae status, valvular leaflet length and coaptation were examined and color Doppler regurgitation jet area was measured. Mitral anulus diameter was 40.2 +/- 8.06 mm (diastolic) and 41.9 +/- 8.53 mm (systolic) and was above the values considered to be normal. Anterior leaflet length was 30.8 +/- 3.12 mm and posterior leaflet length was 22.9 +/- 4.74 mm; regurgitation jet area was between 1.2 cm2 and 13.52 cm2 with an average of 5.44 cm2. In the group with MR of mixomatous origin, systolic anulus diameter showed a linear correlation with regurgitation jet area (r = 0.79). In the 6 patients who underwent cardiac catheterization, angiographic semiquantitative evaluation of the MR confirmed that based on color Doppler jet area. In all twenty patients transesophageal echocardiography enabled us to identify the mechanism responsible for mitral insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Addition of captopril versus increasing diuretics in moderate but deteriorating heart failure: a double-blind comparative trial.

In 15 patients with moderate congestive heart failure not completely controlled on digoxin (0.25 mg o.d.) and frusemide (25 mg o.d.), we compared the addition of captopril (12.5 to 50 mg b.i.d.) with increasing doses of frusemide (25 to 100 mg o.d.), in a randomized double-blind, double-dummy, comparative trial. Thirteen patients completed the 3 months study: two dropped-out in the frusemide group. Statistically significant clinical improvement occurred in both treatment groups. Exercise tolerance also significantly improved in both groups in a parallel fashion. Echocardiographic cardiac function data showed a significantly better pattern of changes in the captopril group. The addition of low doses of captopril to basal therapy seems to be as effective as the addition of high doses of frusemide in uncontrolled moderate congestive heart failure. This approach with captopril also appears to be more physiological and safe.