Functional Analyses of Two Novel LRRK2 Pathogenic Variants in Familial Parkinson's Disease.

BACKGROUND: Pathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinson's disease. However, only seven variants have been confirmed to be pathogenic. OBJECTIVES: We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing. METHODS: We transiently expressed wild-type, the two new variants, or two known pathogenic mutants (G2019S and R1441G) in HEK-293 T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins. RESULTS: The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity. CONCLUSIONS: We identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinson's disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Percutaneous Closure of PFO in Patients with Reduced Oxygen Saturation at Rest and during Exercise: Short- and Long-Term Results.

BACKGROUND: A patent foramen ovale (PFO) is a rare cause of hypoxemia and clinical symptoms of dyspnea. Due to a right-to-left shunt, desaturated blood enters the systemic circulation in a subset of patients resulting in dyspnea and a subsequent reduction in quality of life (QoL). Percutaneous closure of PFO is the treatment of choice. OBJECTIVES: This retrospective multicentre study evaluates short- and long-term results of percutaneous closure of PFO in patients with dyspnea and/or reduced oxygen saturation. METHODS: Patients with respiratory symptoms were selected from databases containing all patients percutaneously closed between January 2000 and September 2018. Improvement in dyspnea, oxygenation, and QoL was investigated using pre- and postprocedural lung function parameters and two postprocedural questionnaires (SF-36 and PFSDQ-M). RESULTS: The average follow-up period was 36 [12-43] months, ranging from 0 months to 14 years. Percutaneous closure was successful in 15 of the 16 patients. All patients reported subjective improvement in dyspnea immediately after device deployment, consistent with their improvement in oxygen saturation (from 90 ± 6% to 94 [92-97%] on room air and in upright position) (p < 0.05). Both questionnaires also indicated an improvement of dyspnea and QoL after closure. The two early and two late deaths were unrelated to the procedure. CONCLUSION: PFO-related dyspnea and/or hypoxemia can be treated successfully with a percutaneous intervention with long-lasting benefits on oxygen saturation, dyspnea, and QoL.

Incomplete coronary sinus reducer endothelialization as potential mechanism of clinical failure.

The number of patients suffering from refractory angina is constantly increasing. Moreover, these patients are considered at higher risk for new hospitalizations and increased incidence of adverse cardiac events. The coronary sinus reducer was recently introduced as a new therapeutic option in patients with refractory angina and no possibilities for coronary revascularization. However, a consistent percentage of patients, ranging from 15 to 30%, reports no clinical benefits after coronary sinus reducer implantation. The reasons for this lack of effectiveness are at present unknown. We suggest here a possible explanation to this phenomenon.

Complete atrioventricular block with diastolic mitral regurgitation due to severe lithium intoxication. A case report.

BACKGROUND: Lithium remains the first line therapy for treatment of bipolar disorder and is widely used in psychiatry despite its narrow therapeutic window. Cardiac side effects are uncommon, but when they are present, they can vary from benign repolarization changes to life threatening tachyarrhythmias as well as conduction time abnormalities. In extremely rare cases complete atrioventricular block with cardiogenic shock can be seen. METHODS: We report the clinical course and outcome of a 79-year-old patient who presented with bradyarrhythmias and a complete atrioventricular block due to severe lithium intoxication. The patient was admitted to ICU where fluid resuscitation and intermittent haemodialysis were performed. Interestingly, the cardiac ultrasound on ICU showed a diastolic mitral regurgitation which was related to the underlying complete atrioventricular block. RESULTS: After two cycles of haemodialysis lithium blood levels were normalised and 24 h later sinus rhythm was restored without any signs of atrioventricular block. The patient recovered completely. CONCLUSION: Lithium is widely used for the treatment of bipolar disorder and it can rarely lead to complete atrioventricular block. If the physician encounters a patient with a history of lithium use, who also shows cardiac arrhythmias, then lithium intoxication should always be ruled out. Haemodialysis is the treatment of choice in severe lithium intoxication. Diastolic mitral regurgitation can hint towards underlying atrioventricular conduction disturbances.

Efficacy and safety of the second-generation cryoballoon ablation for the treatment of persistent atrial fibrillation in elderly patients.

BACKGROUND: It is expected that ablation procedures will be increasingly offered to a more aged population affected with persistent AF (persAF); however, the clinical outcomes of ablation in this specific population are not well described. We aimed to analyze the efficacy and safety of CB-A in this group of patients compared with a younger cohort. METHODS AND RESULTS: Eighty-three patients with (persAF) aged ≥75 years (group 1; mean age 78.2 ± 3.1 years) and 166 patients also affected with persAF aged <75 years (group 2; mean age 64.3 ± 6.6 years) were included in the study. The primary outcome was freedom from recurrent sustained (>30 seconds) atrial arrhythmias without anti-arrhythmic medication after a blanking period of 3 months. At 2 years, clinical success was achieved in 108 out of 249 patients (43.4%). Median follow-up was 24 months (IQR: 18.4-25.5 months). Older patients suffered from more recurrences than those in the younger cohort ((53/83 patients, 63.9% vs 88/166 patients, 53.0%; P = .03). Thirty (12.0%) patients suffered a complication, but the incidence of complications was not different between both groups. The most frequent complication was transient phrenic nerve injury. CONCLUSIONS: The global 2 years efficacy of CB-A PVI in persAF is 43.4%. A lower success rate is achieved in the older patients (36.1%) compared to the younger age group (47.0%). However, the complication rate was not different between age groups.

Rapid Ventricular Pacing for Neurovascular Surgery: A Study on Cardiac and Cerebral Effects.

BACKGROUND AND OBJECTIVE: Intraoperative rupture of a cerebral aneurysm during neurosurgery can be a devastating event that increases perioperative morbidity and mortality. Rapid ventricular pacing (RVP) is a technique to obtain flow arrest for short periods of time during dissection or rupture of the aneurysm. The objective of this study was to evaluate the neurological and cardiac effects of repetitive periods of RVP during cerebrovascular surgery. METHODS: Data from patients who underwent repetitive RVP during craniotomy for cerebrovascular disorders were retrospectively analyzed from a single-center medical records database (Cegeka Medical Health Care Systems). We compared preoperative and postoperative troponin levels (cTnI) to assess cardiac ischemia. Preoperative and postoperative magnetic resonance imaging (MRI) results were screened for RVP-induced infarcts by evaluating diffusion restriction in the hemisphere contralateral to the operated side and the fossa posterior. RESULTS: A total of 37 patients were analyzed. An immediate decrease of systolic arterial blood pressure (<60 mm Hg) was achieved after initiation of RVP. Postoperative MRI did not reveal areas of diffusion restriction. RVP tended to be a predictor of postoperative cTnI increase. Preoperative and postoperative cTnI levels were higher in patients with a subarachnoid hemorrhage compared to patients without one. After 24 hours cTnI jevels normalized to preoperative values. CONCLUSIONS: Systolic arterial blood pressure decreased after RVP but normalized immediately when pacing stopped. MRI of the brain did not show RVP-related ischemia and the limited cTnI level increase normalized to preoperative values. Therefore, RVP during short periods of time seems to be a safe blood pressure-lowering technique for the brain and heart.

Rapid ventricular pacing for flow arrest during cerebrovascular surgery: revival of an old concept.

BACKGROUND: Intraoperative rupture of a cerebral aneurysm can be a devastating event that increases operative morbidity and mortality. Rapid ventricular pacing (RVP) is a technique used in interventional cardiology to obtain flow arrest for short periods of time. OBJECTIVE: To present our experience using RVP for flow arrest during cerebrovascular surgery. METHODS: We used RVP to produce flow arrest for periods of 40 seconds in 12 patients who underwent craniotomy for a cerebrovascular disorder (11 aneurysms and 1 arteriovenous malformation). RESULTS: During RVP, there was an immediate and significant reduction of blood pressure in each patient. The maximum degree of hypotension was obtained 3.2 ± 0.7 seconds (mean ± SD) after the start of RVP. When RVP was terminated, normal sinus rhythm returned instantaneously, along with recovery of indexes of hemodynamic function. Subjectively, the decrease in blood pressures facilitated dissection, and during clipping, the aneurysm sac felt softer and was easier to manipulate. No complications related to RVP occurred. CONCLUSION: Rapid ventricular pacing during cerebrovascular surgery is an effective method for lowering the arterial blood pressure in a controlled and directly reversible manner. Advances in cardiology now make RVP a promising and safe technique that can facilitate complex cerebrovascular surgery.