Candidacy and long-term outcomes of subcutaneous implantable cardioverter-defibrillators in current practice in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with Hypertrophic Cardiomyopathy (HCM) S-ICD is usually the preferred option as pacing is generally not indicated. However, limited data are available on its current practice adoption and long-term follow-up. METHODS: Consecutive HCM patients with S-ICD implanted between 2013 and 2021 in 3 international centers were enrolled in this observational study. Baseline, procedural and follow-up data were regularly collected. Efficacy and safety were compared with a cohort of HCM patients implanted with a tv-ICD. RESULTS: Seventy patients (64% males) were implanted with S-ICD at 41 ± 15 years, whereas 168 patients with tv-ICD at 49 ± 16 years. For S-ICD patients, mean ESC SCD risk score was 4,5 ± 1.9%: 25 (40%) at low-risk, 17 (27%) at intermediate and 20 (33%) at high-risk. Patients were followed-up for 5.1 ± 2.3 years. Two patients (0.6 per 100-person-years, vs 0.4 per 100 person-years with tv-ICD, p = 0.45) received an appropriate shock on VF, 17 (24%) were diagnosed with de-novo AF. Inappropriate shocks occurred in 4 patients (1.2 per 100-person-years, vs 0.9 per 100 person-years with tv-ICD, p = 0.74), all before Smart-Pass algorithm implementation. Four patients experienced device-related adverse events (1.2 per 100-person-years, vs 1 per 100 person-years with tv-ICD, p = 0.35%). CONCLUSIONS: S-ICDs were often implanted in patients with an overall low-intermediate ESC SCD risk, reflecting both the inclusion of additional risk markers and a lower decision threshold. S-ICDs in HCM patients followed for over 5 years showed to be effective in conversion of VF and safe. Greater scrutiny may be required to avoid overtreatment in patients with milder risk profiles.

[Long QT syndrome and Brugada syndrome: 2 aspects of the same disease?]. / Sindrome del QT lungo e sindrome di Brugada: due aspetti della stessa malattia?

In clinical cardiology, resort has recently been made to molecular genetics in order to explain some mechanisms that underlie sudden cardiac death in young people with structurally normal hearts. It has become evident that genetic mutations regarding cardiac ion channels may disrupt the delicate balance of currents in the action potential, thus inducing malignant ventricular tachyarrhythmias. The cardiac sodium channel gene, SCN5A, is involved in two of such arrhythmogenic diseases, the Brugada syndrome and one form of the long QT syndrome (LQT3). It is believed that these syndromes result from opposite molecular effects: Brugada syndrome mutations cause a reduced sodium current, while LQT3 mutations are associated with a gain of function. The effects of class I antiarrhythmic drugs have been used to differentiate these diseases. Intravenous flecainide is used as a highly specific test to unmask the electrocardiographic phenotype of the Brugada syndrome. On the other hand, on the basis of experimental and clinical studies, the possibility that the same drugs act as a gene-specific therapy in this disorder by contrasting the effect of mutations in LQT3 has been explored. Recent evidence shows that phenotypic overlap may exist between the Brugada syndrome and LQT3. One large family with a SCN5A mutation and a "mixed" electrocardiographic pattern (prolonged QT interval and ST-segment elevation) has been reported. Moreover, our recent data showed that flecainide challenge may elicit ST-segment elevation in some LQT3 patients. The presence of "intermediate" phenotypes highlights a remarkable heterogeneity suggesting that clinical features may depend upon the single mutation. Only deepened understanding of the genotype-phenotype correlation will allow the definition of the individual patient's risk and the development of guidelines for clinical management.

Yeast cell permeabilization by osmotic shock allows determination of enzymatic activities in situ.

Yeast cells were permeabilized by incubation in 0.8 M sorbitol followed by suspension in dilute buffer. A preincubation with 2-mercaptoethanol was also included for optimal permeabilization. More than 90% of the treated cells were stainable with methylene blue. Determinations of cell wall-synthesizing enzymes (beta(1 --> 3)glucan and chitin synthases) and cytosolic enzymes in permeabilized cells yielded similar or higher activities than those in cell extracts. With chitin synthase III, the activity obtained with cells was 4- to 6-fold higher than in membrane preparations. Little protein leaks from the cells during permeabilization; yet the cells appear to be readily permeable to substrates and even proteins. Thus, these preparations may be of wide use for the study of enzymes and of biological processes in situ.

Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome: A prospective evaluation of 52 families.

BACKGROUND: The ECG pattern of right bundle branch block and ST-segment elevation in leads V(1) to V(3) (Brugada syndrome) is associated with high risk of sudden death in patients with a normal heart. Current management and prognosis are based on a single study suggesting a high mortality risk within 3 years for symptomatic and asymptomatic patients alike. As a consequence, aggressive management (implantable cardioverter defibrillator) is recommended for both groups. METHODS AND RESULTS: Sixty patients (45 males aged 40+/-15 years) with the typical ECG pattern were clinically evaluated. Events at follow-up were analyzed for patients with at least one episode of aborted sudden death or syncope of unknown origin before recognition of the syndrome (30 symptomatic patients) and for patients without previous history of events (30 asymptomatic patients). Prevalence of mutations of the cardiac sodium channel was 15%, demonstrating genetic heterogeneity. During a mean follow-up of 33+/-38 months, ventricular fibrillation occurred in 5 (16%) of 30 symptomatic patients and in none of the 30 asymptomatic patients. Programmed electrical stimulation was of limited value in identifying patients at risk (positive predictive value 50%, negative predictive value 46%). Pharmacological challenge with sodium channel blockers was unable to unmask most silent gene carriers (positive predictive value 35%). CONCLUSIONS: At variance with current views, asymptomatic patients are at lower risk for sudden death. Programmed electrical stimulation identifies only a fraction of individuals at risk, and sodium channel blockade fails to unmask most silent gene carriers. This novel evidence mandates a reappraisal of therapeutic management.

The elusive link between LQT3 and Brugada syndrome: the role of flecainide challenge.

BACKGROUND: Defects of the SCN5A gene encoding the cardiac sodium channel are associated with both the LQT3 subtype of long-QT syndrome and Brugada syndrome (BS). The typical manifestations of long-QT syndrome (QT interval prolongation) and BS (ST segment elevation in leads V1 through V3) may coexist in the same patients, which raises questions about the actual differences between LQT3 and BS. Intravenous flecainide is the standard provocative test used to unmask BS in individuals with concealed forms of the disease, and oral flecainide has been proposed as a treatment option for LQT3 patients because it may shorten their QT interval. METHODS AND RESULTS: We tested the possibility that in some LQT3 patients, flecainide might not only shorten the QT interval, but also produce an elevation of the ST segment. A total of 13 patients from 7 LQT3 families received intravenous flecainide using the protocol used for BS. As expected, QT, QTc, JT, and JTc interval shortening was observed in 12 of the 13 patients, and concomitant ST segment elevation in leads V1 through V3 (>/=2 mm) was observed in 6 of the 13. CONCLUSIONS: The data demonstrate that flecainide may induce ST segment elevation in LQT3 patients, raising concerns about the safety of flecainide therapy and demonstrating the existence of an intriguing overlap between LQT3 and BS.

Studies of pectic enzymes produced by Talaromyces flavus in submerged and solid substrate cultures.

Tons of peel and rag are generated each year by industries of citrus fruit juices. These by-products are used either for the elaboration of pectin or as substrate for enzyme production. Talaromyces flavus produces extracellular pectinesterase and polygalacturonase after 24 h in submerged culture supplemented with 0.5-0.8% citrus pectin preceded by preculture for 24 h in 2% (w/v) sucrose or in solid substrate culture on passion fruit peel, lemon or orange pulp pellets after 3-6 days of incubation. Chromatographic profiles in a CM-Sepharose column of liquid and solid cultures were very similar, consisting of one endopoligalacturonase (endo-PG I) and one pectinolytic complex constituted by an endopoligalacturonase (endo-PG II) and pectinesterase. Pectin and pectate lyases were undetectable in both media. In Talaromyces flavus the synthesis of pectinases was repressed by glucose and finally controlled by the concentration of products from pectic enzymes degradation.

Regulation of pectic enzymes from the exo-1 mutant strain of Neurospora crassa: effects of glucose, galactose, and galacturonic acid.

The exo-1 mutant of Neurospora crassa produced and secreted pectolytic activities when incubated in the presence of pectin-containing biological materials. This study shows that polygalacturonase, pectate lyase and pectin lyase activities were induced in media supplemented with galactose or galacturonic acid, indicating that these sugars induced the synthesis of pectinases. Pectinesterase activity was undetectable. Polygalacturonase activity was better induced by galactose than by galacturonic acid. The reverse was true for lyase activities. The inducing effect of galactose and galacturonic acid seemed to be different: (i) a mixture of galactose and galacturonic acid synergistically increased the production of pectic enzymes, as compared to that in the presence of one of these sugars; (ii) the inducing effect of galacturonic acid was partially repressed by glucose; (iii) in contrast, the inducing effect of galactose, rather than repressed, was enhanced by the presence of glucose. Altogether, these data point out to a complex mechanism of regulation of pectolytic enzymes by pectin-containing organic substances.