Multidrug resistance transporter-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes.

In brief: Oocyte quality remains the most important and unsolved issue in reproduction. Our data show that multidrug resistance transporters and oocyte mitochondria are involved in determining oocyte quality in a mouse model. Abstract: Multidrug resistance transporter-1 (MDR-1) is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xenobiotics and by-products. Previous findings by our group demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Considering the importance of these organelles in the female gamete, we assessed the impact of MDR-1 dysfunction on mouse oocyte quality, with a particular focus on the meiotic spindle organization, aneuploidies, Ca2+ homeostasis, ATP production and mtDNA mutations. Our results demonstrate that young Mdr1a mutant mice produce oocytes characterized by lower quality, with a significant delay in the germinal vesicle to germinal vesicle breakdown transition, an increased percentage of symmetric divisions, chromosome misalignments and a severely altered meiotic spindle shape compared to the wild types. Mutant oocytes exhibit 7000 more SNPs in the exomic DNA and twice the amount of mitochondrial DNA (mtDNA) SNPs compared to the wild-type ones. Ca2+ analysis revealed the inability of MDR-1 mutant oocytes to manage Ca2+ storage content and oscillations in response to several stimuli, and ATP quantification shows that mutant oocytes trend toward lower ATP levels compared to wild types. Finally, 1-year-old mutant ovaries express a lower amount of SIRT1, SIRT3, SIRT5, SIRT6 and SIRT7 compared to wild-type levels. These results together emphasize the importance of MDR-1 in mitochondrial physiology and highlight the influence of MDR-1 on oocyte quality and ovarian aging.

Left atrial appendage closure: a balanced management of the thromboembolic risk in patients with hemophilia and atrial fibrillation.

Atrial fibrillation is the most common cardiac arrhythmia and is a major cause of embolic stroke. In patients at high bleeding risk such as those with hemophilia, the thromboembolic prevention is challenging. We herein present three patients affected by moderate to severe hemophilia and atrial fibrillation that were treated in our Institution between March 2018 and September 2019, with percutaneous left atrial appendage closure. In patients with relative or absolute contraindications to long-term anticoagulant therapy, the left atrial appendage closure could represent a reasonable strategy.

[Spontaneous coronary dissection complicated by Takotsubo syndrome or Takotsubo syndrome complicated by spontaneous coronary dissection: the complex integration of invasive and non-invasive imaging]. / Dissezione coronarica spontanea complicata da sindrome Takotsubo o sindrome Takotsubo complicata da dissezione coronarica spontanea: quando l'integrazione tra imaging invasivo e non invasivo può essere complessa.

Spontaneous coronary artery dissection syndrome and Takotsubo syndrome are similar entities. They have peculiar features in common, such as a predilection for female sex, signs and symptoms compatible with acute coronary syndrome, high probability of restitutio ad integrum. The interdependence between these two diseases is of intriguing diagnostic and therapeutic implication.A 51-year-old woman presented to our attention with chest pain and evidence of ST-segment elevation. Coronary angiography showed the presence of type 2 dissection involving the diagonal branch. A conservative strategy was preferred. A severe emotional stress conditioned the following hours of hospitalization. A Takotsubo-like pattern was detected at focused echocardiogram. Cardiac magnetic resonance imaging confirmed the typical left ventricular motion abnormalities of a stress cardiomyopathy and T2-weighted sequences showed increased late gadolinium enhancement in the diagonal branch area, leading to the diagnosis of a concomitant coronary dissection and Takotsubo cardiomyopathy.

"Troponinosis", the Cardiologist's Curse-When Clinic-Laboratory Interaction Unveils the Mystery: A Case Report.

Cardiac troponins are key diagnostic and prognostic biomarkers in acute myocardial infarction and, more generally, for the detection of myocardial injury. Since the introduction of the first immunochemistry methods, there has been a remarkable evolution in analytical performance, especially concerning a progressive improvement in sensitivity. However, the measurement of circulating troponins remains rarely susceptible to analytical interferences. We report a case of persistently elevated troponin I concentrations in a patient with known ischemic heart disease, which almost led to unnecessary diagnostic-therapeutic interventions. A prompt laboratory consultation by the cardiologist ultimately led to the identification of an analytical interference due to troponin macrocomplexes (macrotroponin) causing elevated troponin values in the absence of a clinical presentation compatible with myocardial damage.

Quantitative flow ratio-based outcomes in patients undergoing transcatheter aortic valve implantation quaestio study.

Background: Coronary artery disease (CAD) is common in patients with aortic valve stenosis (AS) ranging from 60% to 80%. The clinical and prognostic role of coronary artery lesions in patients undergoing Transcatheter Aortic Valve Implantation (TAVI) remains unclear. The aim of the present observational study was to estimate long-term clinical outcomes by Quantitative Flow Ratio (QFR) characterization of CAD in a well-represented cohort of patients affected by severe AS treated by TAVI. Methods: A total of 439 invasive coronary angiographies of patients deemed eligible for TAVI by local Heart Teams with symptomatic severe AS were retrospectively screened for QFR analysis. The primary endpoint of the study was all-cause mortality. The secondary endpoint was a composite of cardiovascular mortality, stroke/transient ischemic attack (TIA), acute myocardial infarction (AMI), and any hospitalization after TAVI. Results: After exclusion of patients with no follow-up data, coronary angiography not feasible for QFR analysis and previous surgical myocardial revascularization (CABG) 48/239 (20.1%) patients had a QFR value lower or equal to 0.80 (QFR + value), while the remaining 191/239 (79.9%) did not present any vessel with a QFR positive value. In the adjusted Cox regression analysis, patients with positive QFR were independently associated with an increased risk of all-casual mortality (Model 1, HR 3.47, 95% CI, 2.35-5.12; Model 2, HR 5.01, 95% CI, 3.17-7.90). In the adjusted covariate analysis, QFR+ involving LAD (37/48, 77,1%) was associated with the higher risk of the composite outcome compared to patients without any positive value of QFR or non-LAD QFR positive value (11/48, 22.9%). Conclusions: Pre-TAVI QFR analysis can be used for a safe, simple, wireless functional assessment of CAD. QFR permits to identify patients at high risk of cardiovascular mortality or MACE, and it could be considered by local Heart Teams.

Left atrial appendage occlusion in patients with atrial fibrillation and large prevalence of prior intracranial bleeding.

BACKGROUND: Left atrial appendage occlusion (LAAO) represents an alternative approach for the prevention of cardioembolic stroke in patients with nonvalvular atrial fibrillation (NVAF) and contraindication for oral anticoagulation (OAC). The aim of our study was to analyse the outcomes in patients treated with LAAO, with a focus on cases with previous intracranial bleeding. METHODS: Sixty patients with NVAF underwent LAAO (75.4 ±â€Š9 years); mean CHA2DS2-VASc was 4.4 ±â€Š1.7, mean HAS-BLED 3.2 ±â€Š0.9. Thirty-two patients (53.3%) reported previous intracranial bleeding. Ischaemic and bleeding events recorded during follow-up were compared with expected event rates according to CHA2DS2-VASc and HAS-BLED scores. RESULTS: Device implantation was successful in 58 patients (96.7%). The antiplatelet therapy was tailored according to patients' bleeding risk. During follow-up (2.32 ±â€Š1.5 years) 3 ischaemic strokes and 1 transient ischaemic attack occurred, versus 13 total expected thromboembolic events (P = 0.033); 5 major bleedings were observed, versus 7 expected ones, if the patients were under OAC. Considering the combined endpoint (thromboembolic and major bleeding events) 9 events were observed versus 20 expected major events (P = 0.031). In the prespecified subgroup of patients with previous intracranial bleeding, two ischaemic strokes and one transient ischaemic attack were observed during follow-up versus six total expected thromboembolic events; no intracranial bleeding recurrence was recorded. Regarding the combined endpoint four major events were recorded versus nine expected ones. CONCLUSION: LAAO is an efficient and safe option for the prevention of cardioembolic stroke in patients with NVAF, high thromboembolic risk and contraindication to OAC, particularly in patients with previous intracranial bleeding.

The RITMIA™ Smartphone App for Automated Detection of Atrial Fibrillation: Accuracy in Consecutive Patients Undergoing Elective Electrical Cardioversion.

BACKGROUND: The RITMIA™ app (Heart Sentinel™, Parma, Italy) is a novel application that combined with a wearable consumer-grade chest-strap Bluetooth heart rate monitor, provides automated detection of atrial fibrillation (AF), and may be promising for sustainable AF screening programs, since it is known that prolonged monitoring leads to increased AF diagnosis. OBJECTIVE: The purpose of this study was to examine whether RITMIA™ could accurately differentiate sinus rhythm (SR) from AF compared with gold-standard physician-interpreted 12-lead electrocardiogram (ECG). DESIGN: In this observational prospective study consecutive patients presenting for elective cardioversion (ECV) of AF, from November 2017 to November 2018, were enrolled. Patients underwent paired 12-lead ECG and RITMIA™ recording, both before and after ECV procedure. The RITMIA™ automated interpretation was compared with 12-lead ECG interpreted by the agreement of two cardiologists. The latter were blinded to the results of the App automated diagnosis. Feasibility, sensitivity, specificity, and K coefficient for RITMIA™ automated diagnosis were calculated. RESULTS: A total of 100 consecutive patients were screened and enrolled. Five patients did not undergo ECV due to spontaneous restoration of SR. 95 patients who actually underwent ECV were included in the final analysis. Mean age was 66.2±10.7 years; female patients were 20 (21.1%). There were 190 paired ECGs and RITMIA™ recordings. The RITMIA™ app correctly detected AF with 97% sensitivity, 95.6% specificity, and a K coefficient of 0.93. CONCLUSIONS: The automated RITMIA™ algorithm very accurately differentiated AF from SR before and after elective ECV. The only hardware required by this method is a cheap consumer-grade Bluetooth heart rate monitor of the chest-strap type. This robust and affordable RITMIA™ technology could be used to conduct population-wide screening in patients at risk for silent AF, thanks to the long-term monitoring applicability.

[Percutaneous left atrial appendage closure in a patient with atrial fibrillation and Rendu-Osler-Weber disease]. / Chiusura percutanea dell'auricola sinistra in paziente con fibrillazione atriale e malattia di Rendu-Osler-Weber.

Atrial fibrillation is the most common cardiac arrhythmia worldwide and represents a major risk factor for cerebral embolic stroke. The standard therapy in the prevention of stroke is oral anticoagulation therapy (OAT). However, a considerable number of patients are unable to tolerate chronic OAT. Among these are patients with hereditary hemorrhagic telangiectasia. We present the case of a female patient affected by Rendu-Osler-Weber disease and atrial fibrillation with indication to OAT. Because of worsening bleeding episodes, this therapy was discontinued and we decided to perform percutaneous left atrial appendage occlusion (LAAO) with implantation of the WATCHMAN device (Boston Scientific). Post-procedural antithrombotic therapy with clopidogrel 75 mg/day was prematurely interrupted after 3 weeks because of significant bleeding recurrences. After 12 months, the patient is in good health, with rare episodes of minor bleeding. Echocardiography showed a well-positioned LAAO device, without thrombotic apposition. In conclusion, this case confirms that percutaneous LAAO is a valid therapeutic alternative to OAT and represents a successful strategy in high bleeding risk patients with a contraindication to OAT. By thorough assessment, a single antiplatelet therapy after device implantation and for a time-limited period might be considered, according to the latest recent evidence.

Serum uric acid level predicts adverse outcomes after myocardial revascularization or cardiac valve surgery.

Background High levels of serum uric acid have been associated with adverse outcomes in cardiovascular diseases such as myocardial infarction and heart failure. The aim of the current study was to evaluate the prognostic role of serum uric acid levels in patients undergoing cardiac rehabilitation after myocardial revascularization and/or cardiac valve surgery. Design We performed an observational prospective cohort study. Methods The study included 1440 patients with available serum uric acid levels, prospectively followed for 50 ± 17 months. Mean age was 67 ± 11 years; 781 patients (54%) underwent myocardial revascularization, 474 (33%) cardiac valve surgery and 185 (13%) valve-plus-coronary artery by-pass graft surgery. The primary endpoints were overall and cardiovascular mortality while secondary end-points were combined major adverse cardiac and cerebrovascular events. Results Serum uric acid level mean values were 286 ± 95 µmol/l and elevated serum uric acid levels (≥360 µmol/l or 6 mg/dl) were found in 275 patients (19%). Overall mortality (hazard ratio = 2.1; 95% confidence interval: 1.5-3.0; p < 0.001), cardiovascular mortality (hazard ratio = 2.0; 95% confidence interval: 1.2-3.2; p = 0.004) and major adverse cardiac and cerebrovascular events rate (hazard ratio = 1.5; 95% confidence interval: 1.0-2.0; p = 0.019) were significantly higher in patients with elevated serum uric acid levels, even after adjustment for age, gender, arterial hypertension, diabetes, glomerular filtration rate, atrial fibrillation and medical therapy. Moreover, strong positive correlations between serum uric acid level and probability of overall mortality ( p < 0.001), cardiovascular mortality ( p < 0.001) and major adverse cardiac and cerebrovascular events ( p = 0.003) were found. Conclusions Serum uric acid levels predict mortality and adverse cardiovascular outcome in patients undergoing myocardial revascularization and/or cardiac valve surgery even after the adjustment for age, gender, arterial hypertension, diabetes, glomerular filtration rate and medical therapy.