1,721,090 research outputs found
Functional characterization of a newly identified LMNA mutant in HL-1 cardiomyocytes
No full textA novel mutation in the Lamin A/C gene (LMNA c.418_438dup) was detected in the index patient and in additional family members with diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) and history of sudden cardiac death. The functional characterization of this LMNA mutant was performed in cultured HL-1 cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs and subjected to confocal microscopy analysis and hypoxic stress conditions in 100% N2 for 8h. Mutated LMNA was clearly expressed in aggregates of different sizes and not uniformly distributed along the nuclear envelope as WT LMNA. Moreover, the mutated LMNA variant causes perturbation in nuclear shape and Nuclear Pore Complexes organization. Of note, we observed that under hypoxic conditions nuclear envelopes expressing mutated LMNA become leaky, leading a nuclear fluorescent marker to escape into the cytoplasm. This indicates that, under cell stressing conditions, the nucleo-cytoplasmic compartmentalization is affected in cardiomyocytes expressing this LMNA mutation, inducing, as final fatal consequence, cell apoptosis. In conclusion, we not only open new avenues to gain more insights in the pathogenesis of ARVC and to conceive novel therapeutic strategies but we also shed lights on the role of nuclear Lamin A in the physio-pathology of cardiomyocytes
Ranolazine-Induced Type 1 Brugada Pattern
No full textBackground: Brugada syndrome (BrS) is a rare inherited arrhythmia disease carrying a variable risk of sudden cardiac death. Diagnosis requires the type 1 Brugada electrocardiographic pattern, which can either be spontaneous or induced by sodium channel-blocking drugs. Ranolazine is an antianginal drug acting on the late sodium current with emerging antiarrhythmic properties; no information is available on the safety of ranolazine use in patients with BrS. Case Summary: We present the case of a 48-year-old man with recent history of ST-elevation myocardial infarction and residual microvascular angina who developed a type 1 Brugada pattern after starting therapy with ranolazine. Discussion: Ranolazine has been demonstrated to be effective as an antiarrhythmic drug in several conditions in which other sodium-channel blockers are currently employed (eg, atrial fibrillation and type 3 long QT syndrome). Given the mechanism of action, it is plausible to hypothesize a potential role of ranolazine in unmasking the type 1 Brugada pattern. Take-Home Messages: Evidence of the safety of ranolazine in patients with BrS is lacking. A possible connection between ranolazine assumption and the unmasking of a type 1 Brugada pattern may question its use in these patients
Impaired arterial baroreflex function before nitrate-induced vasovagal syncope during head-up tilt test
No full textAims: The aim of this study was to evaluate arterial baroreflex control of heart rate immediately before head-up tilt test (HUT)-induced vasovagal syncope (VVS). Methods and results: We enrolled 97 otherwise healthy subjects with recurrent unexplained syncope. After 10 min of rest in supine position, they underwent a passive HUT potentiated with nitroglycerin administration after 20 min. Beat-to-beat heart rate and systolic blood pressure were continuously recorded. Sequence method was used to measure two complementary parameters reflecting arterial baroreflex control of heart rate: the baroreflex sensitivity (BRS) and the baroreflex effectiveness index (BEI). Twenty-one patients fainted before nitrate administration (HUT+) and 37 after nitrate administration (NTG+). Immediately before syncope, the NTG+ patients showed significantly lower BRS values than those observed at the end of the test in the patients without syncope (5.5 ± 2.8 vs. 7.7 ± 3.4 ms/mmHg; P = 0.004) and a significantly lower BEI (30 ± 20% vs. 53 ± 24%; P < 0.001). The HUT+ patients did not show any significant differences in BRS and BEI before syncope from the values observed during the corresponding tilt period in the other groups. Conclusion: A significant depression in BRS and BEI occurs immediately before syncope in patients who faint after nitrate administration, thus suggesting that arterial baroreflex dysfunction plays a role in mediating nitrate-induced VVS
Independent role of reduced arterial baroreflex sensitivity during head-up tilt testing in predicting vasovagal syncope recurrence
No full textAims The involvement of arterial baroreflex function in the pathophysiology of vasovagal syncope (VVS) is controversial, and there are no published data supporting its clinical usefulness. The aim of this study was to evaluate the role of arterial baroreflex sensitivity (BRS) at baseline and during head-up tilt testing (HUT) in predicting the recurrence of VVS. Methods and results The study involved otherwise healthy patients with a history of unexplained syncope who underwent diagnostic HUT by being tilted to 70° after 10 min supine rest; the test was potentiated by the administration of 300 g of nitroglycerine (NTG) after 20 min. Beat-to-beat heart rate and systolic blood pressure were continuously recorded, and the sequence method was used to measure arterial baroreflex control of heart rate. The 190 enrolled patients were followed up for 18 ± 6 months, during which 34 experienced a total of 90 episodes of syncope recurrence. In a stepwise multivariate analysis, female gender [hazard ratio (HR): 2.74; P = 0.008], the presence of ≥3 syncope events before HUT (HR: 3.36; P = 0.004), and BRS below median value after the start of HUT or after the administration of NTG (HR: 3.79; P = 0.006) were significantly and independently associated with the recurrence of syncope. Moreover, when a BRS value of less than the median was added to the other independent factors in a stepwise model, a significant increase in discrimination (C-index: 0.77) and model fitting (P = 0.001) was observed. Conclusion Reduced BRS during HUT has independent and incremental value in predicting the recurrence of syncope, thus supporting its potential usefulness in the clinical management of patients
The expression of Lamin A mutant R321X leads to endoplasmic reticulum stress with aberrant Ca(2+) handling
No full textMutations in the Lamin A/C gene (LMNA), which encodes A-type nuclear Lamins, represent the most frequent genetic cause of dilated cardiomyopathy (DCM). This study is focused on a LMNA nonsense mutation (R321X) identified in several members of an Italian family that produces a truncated protein isoform, which co-segregates with a severe form of cardiomyopathy with poor prognosis. However, no molecular mechanisms other than nonsense mediated decay of the messenger and possible haploinsufficiency were proposed to explain DCM. Aim of this study was to gain more insights into the disease-causing mechanisms induced by the expression of R321X at cellular level. We detected the expression of R321X by Western blotting from whole lysate of a mutation carrier heart biopsy. When expressed in HEK293 cells, GFP- (or mCherry)-tagged R321X mislocalized in the endoplasmic reticulum (ER) inducing the PERK-CHOP axis of the ER stress response. Of note, confocal microscopy showed phosphorylation of PERK in sections of the mutation carrier heart biopsy. ER mislocalization of mCherry-R321X also induced impaired ER Ca(2+) handling, reduced capacitative Ca(2+) entry at the plasma membrane and abnormal nuclear Ca(2+) dynamics. In addition, expression of R321X by itself increased the apoptosis rate. In conclusion, R321X is the first LMNA mutant identified to date, which mislocalizes into the ER affecting cellular homeostasis mechanisms not strictly related to nuclear functions
The expression of Lamin A mutant R321X leads to endoplasmic reticulum stress with aberrant Ca(2+) handling
Full text linkMutations in the Lamin A/C gene (LMNA), which encodes A-type nuclear Lamins, represent the most frequent genetic cause of dilated cardiomyopathy (DCM). This study is focused on a LMNA nonsense mutation (R321X) identified in several members of an Italian family that produces a truncated protein isoform, which co-segregates with a severe form of cardiomyopathy with poor prognosis. However, no molecular mechanisms other than nonsense mediated decay of the messenger and possible haploinsufficiency were proposed to explain DCM. Aim of this study was to gain more insights into the disease-causing mechanisms induced by the expression of R321X at cellular level. We detected the expression of R321X by Western blotting from whole lysate of a mutation carrier heart biopsy. When expressed in HEK293 cells, GFP- (or mCherry)-tagged R321X mislocalized in the endoplasmic reticulum (ER) inducing the PERK-CHOP axis of the ER stress response. Of note, confocal microscopy showed phosphorylation of PERK in sections of the mutation carrier heart biopsy. ER mislocalization of mCherry-R321X also induced impaired ER Ca(2+) handling, reduced capacitative Ca(2+) entry at the plasma membrane and abnormal nuclear Ca(2+) dynamics. In addition, expression of R321X by itself increased the apoptosis rate. In conclusion, R321X is the first LMNA mutant identified to date, which mislocalizes into the ER affecting cellular homeostasis mechanisms not strictly related to nuclear functions
Cardiomyopathies and Psychiatric Disorders: An Overview and General Clinical Recommendations
Full text linkThe association between cardiomyopathies (CMPs) and psychiatric disorders is a complex and bidirectional phenomenon that involves multiple mechanisms and factors. CMPs may raise the risk of psychiatric disorders due to the psychological stress, physical limitations, social isolation, or poor prognosis associated with the underlying disease. Psychiatric disorders, on the other hand, can increase the possibility of developing or worsening CMPs due to the behavioral, neuroendocrine, inflammatory, or pharmacological effects of mental illness or its treatment. Moreover, some common genetic or environmental factors may have a relevant influence on both conditions. With this comprehensive review, we sought to provide an overview of the current evidence on the strict and intriguing interconnection between CMPs and psychiatric disorders, focusing on the epidemiology, pathophysiology, clinical implications, and management strategies
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