Role of CES1 and ABCB1 Genetic Polymorphisms on Functional Response to Dabigatran in Patients with Atrial Fibrillation.

Background: Dabigatran etexilate is a pro-drug hydrolyzed into dabigatran by carboxylesterases (CES) and is a substrate of the P-Glycoprotein encoded by the adenosine-triphosphate-binding cassette sub-family B member (ABCB)1 genes. We evaluated the functional response to dabigatran according to different CES1 and ABCB1 single-nucleotide polymorphisms (SNPs) in patients with atrial fibrillation (AF). Methods: A total of 100 consecutive patients with AF taking dabigatran were enrolled by two Italian centers. A venous blood sample was drawn for genetic determinations, as well as a measurement of the diluted thrombin time (dTT) and drug plasma concentrations, at the trough and peak. The main objective was the relationship between the dTT values and CES1 rs2244613, CES1 rs8192935 and ABCB1 rs4148738 SNP while on two different dabigatran doses (110 and 150 mg BID). Results: A total of 43 patients were on a 110 mg dabigatran dose and 57 on 150 mg. The DTT values at the trough and at peak were not different among patients with different CES1 rs2244613 and CES1 rs8192935 genotypes, regardless of the dabigatran dose. In patients on 150 mg dabigatran, the dTT values at the trough were 77 (44-111) ng/mL in patients with the ABCB1 rs4148738 heterozygous CT genotype vs. 127 (85-147) ng/mL in the wild-type CC genotype vs. 110 (47-159) ng/mL in the mutant trait TT genotype (p = 0.048). In patients with the ABCB1 rs4148738 CT genotype, OR for having dTT values at a trough below the median was 3.21, 95% CI 1.04-9.88 (p = 0.042). Conclusions: ABCB1 rs4148738 CT heterozygous is associated with the reduced anticoagulant activity of dabigatran at the trough in patients receiving the higher dose regimen.

On site cardiac surgery for structural heart interventions: a fence to mend?

Current evidence supports device-based transcatheter interventions for the management of patients with structural heart disease, proving well their safety and efficacy; transcatheter aortic valve implantation (TAVI), transcatheter edge-to-edge repair (TEER) of mitral or tricuspid valves, and left atrial appendage occlusion (LAAO) are expanding their role in contemporary practice. Currently, guidelines recommend performing TAVI in 'Heart Valve Center' with interventional cardiology and institutional on-site cardiac surgery (iOSCS), while no site limitation has been defined for TEER and LAAO. The growing number of candidates for transcatheter interventions generates long waiting times with negative consequences on mortality, morbidity, hospitalization, and functional deterioration. Therefore, a debate on the feasibility of TAVI in centres without iOSCS has been set up. Data from randomized controlled trials and registries failed to document any difference in outcomes and in conversion rate to emergent surgical bailout in centres with or without iOSCS; on the other hand, a direct relationship with TAVI complications has been clearly documented for learning curve and centre volume. Therefore, the role of iOSCS for TAVI, as well as for other transcatheter interventions, should be carefully explored.

Clinical outcome with different doses of low-molecular-weight heparin in patients hospitalized for COVID-19.

A pro-thrombotic milieu and a higher risk of thrombotic events were observed in patients with CoronaVirus disease-19 (COVID-19). Accordingly, recent data suggested a beneficial role of low molecular weight heparin (LMWH), but the optimal dosage of this treatment is unknown. We evaluated the association between prophylactic vs. intermediate-to-fully anticoagulant doses of enoxaparin and in-hospital adverse events in patients with COVID-19. We retrospectively included 436 consecutive patients admitted in three Italian hospitals. Outcome according to the use of prophylactic (4000 IU) vs. higher (> 4000 IU) daily dosage of enoxaparin was evaluated. The primary end-point was in-hospital death. Secondary outcome measures were in-hospital cardiovascular death, venous thromboembolism, new-onset acute respiratory distress syndrome (ARDS) and mechanical ventilation. A total of 287 patients (65.8%) were treated with the prophylactic enoxaparin regimen and 149 (34.2%) with a higher dosing regimen. The use of prophylactic enoxaparin dose was associated with a similar incidence of all-cause mortality (25.4% vs. 26.9% with the higher dose; OR at multivariable analysis, including the propensity score: 0.847, 95% CI 0.400-0.1.792; p = 0.664). In the prophylactic dose group, a significantly lower incidence of cardiovascular death (OR 0.165), venous thromboembolism (OR 0.067), new-onset ARDS (OR 0.454) and mechanical intubation (OR 0.150) was observed. In patients hospitalized for COVID-19, the use of a prophylactic dosage of enoxaparin appears to be associated with similar in-hospital overall mortality compared to higher doses. These findings require confirmation in a randomized, controlled study.

The 'dreaded PFO': anatomical and functional features of high risk for stroke.

Patent foramen ovale (PFO) has a high prevalence in general population and can be implicated in cryptogenic stroke among young people. Recent trials have shown that transcatheter PFO closure is superior to medical treatment in the secondary prevention of ischaemic stroke. The benefit in the reduction of stroke recurrence is particularly evident in patients who have documentation of a PFO with high-risk characteristics. Therefore, after the assessment of a clear causal relationship with the event, a thoughtful documentation of anatomic (height, length, presence of an aneurysmatic or a floppy atrial septum, a prominent Eustachian valve or Chiari's network, an acute angle with the inferior vena cava) and functional high-risk characteristics is mandatory.

Risk of Atrial Fibrillation in Masked and White Coat Uncontrolled Hypertension.

BACKGROUND: Risk of atrial fibrillation (AF) in masked and white coat uncontrolled hypertension (MUCH and WUCH, respectively) has not yet been investigated. We assessed the risk of new-onset AF in MUCH and WUCH detected by ambulatory blood pressure (BP) monitoring. METHODS: The occurrence of AF was evaluated in 2,135 treated hypertensive patients aged >40 years, with baseline sinus rhythm, by electrocardiogram. Controlled hypertension (CH) was defined as clinic BP <140/90 mm Hg and daytime BP, regardless of nighttime BP, <135/85 mm Hg, MUCH as clinic BP <140/90 mm Hg and daytime BP ≥135 and/or ≥85 mm Hg, WUCH as clinic BP ≥140 and/or ≥90 mm Hg and daytime BP <135/85 mm Hg, and sustained uncontrolled hypertension (SUCH) as clinic BP ≥140 and/or ≥90 mm Hg and daytime BP ≥135 and/or ≥85 mm Hg. RESULTS: MUCH was identified in 203 patients (9.5% of all the population, 29% of those with normal clinic BP) and WUCH in 503 patients (23.5% of all the population, 35% of those with high clinic BP). During the follow-up (mean 9.7 years), 116 cases of AF occurred. After adjustment for covariates, patients with MUCH (hazard ratio 2.02, 95% confidence interval, 1.06-3.85) and SUCH (hazard ratio 1.83, 95% confidence interval, 1.04-3.21) had higher risk of new-onset AF than those with CH, whereas those with WUCH (hazard ratio 1.12, 95% confidence interval, 0.59-2.13) did not. CONCLUSIONS: When compared with patients with CH, those with MUCH and SUCH are at higher risk (approximately doubled) of new-onset AF, whereas those with WUCH are not.