Rare ACTN2 Frameshift Variants Resulting in Protein Extension Cause Distal Myopathy and Hypertrophic Cardiomyopathy through Protein Aggregation.

Distal myopathies are a group of rare, inherited muscular disorders characterized by progressive loss of muscle fibers that begins in the distal parts of arms and legs. Recently, variants in a new disease gene, ACTN2 , have been shown to cause distal myopathy. ACTN2 , a gene previously only associated with cardiomyopathies, encodes alpha-actinin-2, a protein expressed in both cardiac and skeletal sarcomeres. The primary function of alpha-actinin-2 is to link actin and titin to the sarcomere Z-disk. New ACTN2 variants are continuously discovered, however, the clinical significance of many variants remains unknown. Thus, lack of clear genotype-phenotype correlations in ACTN2 -related diseases, actininopathies, persists. Objective: The objective of the study is to characterize the pathomechanisms underlying actininopathies. Methods: Functional characterization in C2C12 cell models of several ACTN2 variants is conducted, including frameshift and missense variants associated with dominant actininopathies. We assess the genotype-phenotype correlations of actininopathies using clinical data from several patients carrying these variants. Results: The results show that the missense variants associated with a recessive form of actininopathy do not cause detectable alpha-actinin-2 aggregates in the cell model. Conversely, dominant frameshift variants causing a protein extension do produce alpha-actinin-2 aggregates. Interpretation: The results suggest that alpha-actinin-2 aggregation is the disease mechanism underlying some dominant actininopathies, and thus we recommend that protein-extending frameshift variants in ACTN2 should be classified as pathogenic. However, this mechanism is likely elicited by only a limited number of variants. Alternative functional characterization methods should be explored to further investigate other molecular mechanisms underlying actininopathies.

Mechanical complications in ST-elevation myocardial infarction: The impact of pre-hospital delay.

AIMS: Mechanical complications (MC) (i.e., free wall rupture (FWR), papillary muscle rupture (PMR) and ventricular septal rupture (VSR)) are rare complications of ST- elevation acute myocardial infarction (STEMI). Incidence of MC according to pre-hospital delay remains unknown. We aimed to determine the rates of MC according to pre-hospital delay. METHODS: Analysis was conducted on the MODIF registry data. Patients were allocated to four groups according to pre-hospital delay: 0 to 12 h, 12 to 24 h, 24 to 36 h and 36 to 48 h. RESULTS: 6185 patients with complete data were analyzed. Mean age was 64.1 years old and 75.7% of patients were males. Eighty-three patients (1.34%) presented with MC: 44 (0.71%) experienced a FWR, 17 (0.27%) a PMR, and 22 (0.36%) a VSR. Global rates of MC were 0.82%, 1.43%, 1.24% and 5.07% in the four groups of pre-hospital delays - 0 to 12 h, 12 to 24 h, 24 to 36 h and 36 to 48 h - respectively (p < 0.001). In-hospital mortality rates were high: 44.2%, 47.1% and 54.6% for FWR, PMR and VSR, respectively. In multivariate analysis, factors independently related to the occurrence of MC were older age, female sex, simultaneous COVID-19 infection, absence of dyslipidemia, initial TIMI flow 0 or 1 in the culprit artery, 36 to 48 h-pre-hospital delay and absence of revascularization by percutaneous coronary intervention (PCI) with stent implantation. CONCLUSION: The probability of MC in STEMI increases with pre-hospital delay. Mechanical complications of STEMI remain associated with a very poor prognosis.

Comparison of clockwise and counterclockwise right atrial flutter using high-resolution mapping and automated velocity measurements.

BACKGROUND: Only few studies have been performed that explore the electrophysiological differences between clockwise (CW) and counterclockwise (CCW) right atrial (RA) cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) using the high-resolution Rhythmia mapping system. OBJECTIVES: We sought to compare CW and CCW CTI-dependent AFL in pure right AFL patients (pts) using the ultra-high-definition (ultra-HD) Rhythmia mapping system and we mathematically developed a cartography model based on automatic velocity RA measurements to identify electrophysiological AFL specificities. METHODS AND RESULTS: Thirty-three pts were recruited. The mean age was 71 ± 13 years old. The sinus venosus (SV) block line was present in 32/33 of cases (97%) and no significant difference was found between CCW and CW CTI AFL (100% vs. 91%; p = .7). No line was localized in the region of the crista terminalis (CT). A superior gap was present in the posterior line in 14/31 (45.2%) but this was similarly present in CCW AFL, when compared to CW AFL (10/22 [45.5%] vs. 4/10 [40%]; p = .9). When present, the extension of the posterior line of block was observed in 18/31 pts (58%) without significant differences between CCW and CW CI AFL (12/22 [54.5%] vs. 6/10 [60%]; p = .9) The Eustachian ridge line of block was similarly present in both groups (82% [18/22] vs. 45.5% [5/11]; p = .2). The absence of the Eustachian ridge line of block led to significantly slowed velocity in this area (28 ± 10 cm/s; n = 8), and the velocities were similarly altered between both groups (26 ± 10 [4/22] vs. 29.8 ± 11 cm/s [4/11]; p = .6). We created mathematical, three-dimensional RA reconstruction-velocity model measurements. In each block localization, when the block line was absent, velocity was significantly slowed (≤20 cm/s). A systematic slowdown in conduction velocity was observed at the entrance and exit of the CTI in 100% of cases. This alteration to the conduction entrance was localized at the lateral side of the CTI for the CCW AFL and at the septal side of the CTI for CW AFL. The exit-conduction alteration was localized at the CTI septal side for the CCW AFL and at the CTI lateral side for the CW AFL. CONCLUSION: The ultra-HD Rhythmia mapping system confirmed the absence of significant electrophysiological differences between CCW and CW AFL. The mechanistic posterior SV and Eustachian ridge block lines were confirmed in each arrhythmia. A systematic slowing down at the entrance and exit of the CTI was demonstrated in both CCW and CW AFL, but in reverse positions.

ST-segment elevation myocardial infarction: Management and association with prognosis during the COVID-19 pandemic in France.

BACKGROUND: Systems of care have been challenged to control progression of the COVID-19 pandemic. Whether this has been associated with delayed reperfusion and worse outcomes in French patients with ST-segment elevation myocardial infarction (STEMI) is unknown. AIM: To compare the rate of STEMI admissions, treatment delays, and outcomes between the first peak of the COVID-19 pandemic in France and the equivalent period in 2019. METHODS: In this nationwide French survey, data from consecutive STEMI patients from 65 centres referred for urgent revascularization between 1 March and 31 May 2020, and between 1 March and 31 May 2019, were analysed. The primary outcome was a composite of in-hospital death or non-fatal mechanical complications of acute myocardial infarction. RESULTS: A total of 6306 patients were included. During the pandemic peak, a 13.9±6.6% (P=0.003) decrease in STEMI admissions per week was observed. Delays between symptom onset and percutaneous coronary intervention were longer in 2020 versus 2019 (270 [interquartile range 150-705] vs 245 [140-646]min; P=0.013), driven by the increase in time from symptom onset to first medical contact (121 [60-360] vs 150 [62-420]min; P=0.002). During 2020, a greater number of mechanical complications was observed (0.9% vs 1.7%; P=0.029) leading to a significant difference in the primary outcome (112 patients [5.6%] in 2019 vs 129 [7.6%] in 2020; P=0.018). No significant difference was observed in rates of orotracheal intubation, in-hospital cardiac arrest, ventricular arrhythmias and cardiogenic shock. CONCLUSIONS: During the first peak of the COVID-19 pandemic in France, there was a decrease in STEMI admissions, associated with longer ischaemic time, exclusively driven by an increase in patient-related delays and an increase in mechanical complications. These findings suggest the need to encourage the population to seek medical help in case of symptoms.

Pulmonary embolism in COVID-19 patients: a French multicentre cohort study.

AIMS: While pulmonary embolism (PE) appears to be a major issue in COVID-19, data remain sparse. We aimed to describe the risk factors and baseline characteristics of patients with PE in a cohort of COVID-19 patients. METHODS AND RESULTS: In a retrospective multicentre observational study, we included consecutive patients hospitalized for COVID-19. Patients without computed tomography pulmonary angiography (CTPA)-proven PE diagnosis and those who were directly admitted to an intensive care unit (ICU) were excluded. Among 1240 patients (58.1% men, mean age 64 ± 17 years), 103 (8.3%) patients had PE confirmed by CTPA. The ICU transfer and mechanical ventilation were significantly higher in the PE group (for both P < 0.001). In an univariable analysis, traditional venous thrombo-embolic risk factors were not associated with PE (P > 0.05), while patients under therapeutic dose anticoagulation before hospitalization or prophylactic dose anticoagulation introduced during hospitalization had lower PE occurrence [odds ratio (OR) 0.40, 95% confidence interval (CI) 0.14-0.91, P = 0.04; and OR 0.11, 95% CI 0.06-0.18, P < 0.001, respectively]. In a multivariable analysis, the following variables, also statistically significant in univariable analysis, were associated with PE: male gender (OR 1.03, 95% CI 1.003-1.069, P = 0.04), anticoagulation with a prophylactic dose (OR 0.83, 95% CI 0.79-0.85, P < 0.001) or a therapeutic dose (OR 0.87, 95% CI 0.82-0.92, P < 0.001), C-reactive protein (OR 1.03, 95% CI 1.01-1.04, P = 0.001), and time from symptom onset to hospitalization (OR 1.02, 95% CI 1.006-1.038, P = 0.002). CONCLUSION: PE risk factors in the COVID-19 context do not include traditional thrombo-embolic risk factors but rather independent clinical and biological findings at admission, including a major contribution to inflammation.