Right Atrial Remodeling and Outcome in Patients with Secondary Tricuspid Regurgitation.

BACKGROUND: In patients with secondary tricuspid regurgitation (STR), right atrial remodeling (RAR) is a proven marker of disease progression. However, the prognostic value of RAR, assessed by indexed right atrial volume (RAVi) and reservoir strain (RAS), remains to be clarified. Accordingly, the aim of our study is to investigate the association with outcome of RAR in patients with STR. METHODS: We enrolled 397 patients (44% men, 72.7 ± 13 years old) with mild to severe STR. Complete two-dimensional and speckle-tracking echocardiography analysis of right atrial and right ventricular (RV) size and function were obtained in all patients. The primary end point was the composite of death from any cause and heart failure hospitalization. RESULTS: After a median follow-up of 15 months (interquartile range, 6-23), the end point was reached by 158 patients (39%). Patients with RAS <13% and RAVi >48 mL/m2 had significantly lower survival rates compared to patients with RAS ≥13% and RAVi ≤48 mL/m2 (log-rank P < .001). On multivariable analysis, RAS <13% (hazard ratio, 2.11; 95% CI, 1.43-3.11; P < .001) and RAVi > 48 mL/m2 (hazard ratio, 1.49; 95% CI, 1.01-2.18; P = .04) remained associated with the combined end point, even after adjusting for RV free-wall longitudinal strain, significant chronic kidney disease, and New York Heart Association class. Secondary tricuspid regurgitation excess mortality increased exponentially with values of 18.2% and 51.3 mL/m2 for RAS and RAVi, respectively. In nested models, the addition of RAS and RAVi provided incremental prognostic value over clinical, conventional echocardiographic parameters of RV size and function and RV free-wall longitudinal strain. CONCLUSIONS: In patients with STR, RAR was independently associated with mortality and heart failure hospitalization. Assessment of RAR could improve risk stratification of patients with STR, potentially identifying those who may benefit from optimization of medical therapy and a closer follow-up.

Electrocardiographic temporo-spatial assessment of depolarization and repolarization changes after epicardial arrhythmogenic substrate ablation in Brugada syndrome.

Aims: In Brugada syndrome (BrS), with spontaneous or ajmaline-induced coved ST elevation, epicardial electro-anatomic potential duration maps (epi-PDMs) were detected on a right ventricle (RV) outflow tract (RVOT), an arrhythmogenic substrate area (AS area), abolished by epicardial-radiofrequency ablation (EPI-AS-RFA). Novel CineECG, projecting 12-lead electrocardiogram (ECG) waveforms on a 3D heart model, previously localized depolarization forces in RV/RVOT in BrS patients. We evaluate 12-lead ECG and CineECG depolarization/repolarization changes in spontaneous type-1 BrS patients before/after EPI-AS-RFA, compared with normal controls. Methods and results: In 30 high-risk BrS patients (93% males, age 37 + 9 years), 12-lead ECGs and epi-PDMs were obtained at baseline, early after EPI-AS-RFA, and late follow-up (FU) (2.7-16.1 months). CineECG estimates temporo-spatial localization during depolarization (Early-QRS and Terminal-QRS) and repolarization (ST-Tpeak, Tpeak-Tend). Differences within BrS patients (baseline vs. early after EPI-AS-RFA vs. late FU) were analysed by Wilcoxon signed-rank test, while differences between BrS patients and 60 age-sex-matched normal controls were analysed by the Mann-Whitney test. In BrS patients, baseline QRS and QTc durations were longer and normalized after EPI-AS-ATC (151 ± 15 vs. 102 ± 13 ms, P < 0.001; 454 ± 40 vs. 421 ± 27 ms, P < 0.000). Baseline QRS amplitude was lower and increased at late FU (0.63 ± 0.26 vs. 0.84 ± 13 ms, P < 0.000), while Terminal-QRS amplitude decreased (0.24 ± 0.07 vs. 0.08 ± 0.03 ms, P < 0.000). At baseline, CineECG depolarization/repolarization wavefront prevalently localized in RV/RVOT (Terminal-QRS, 57%; ST-Tpeak, 100%; and Tpeak-Tend, 61%), congruent with the AS area on epi-PDM. Early after EPI-AS-RFA, RV/RVOT localization during depolarization disappeared, as Terminal-QRS prevalently localized in the left ventricle (LV, 76%), while repolarization still localized on RV/RVOT [ST-Tpeak (44%) and Tpeak-Tend (98%)]. At late FU, depolarization/repolarization forces prevalently localized in the LV (Terminal-QRS, 94%; ST-Tpeak, 63%; Tpeak-Tend, 86%), like normal controls. Conclusion: CineECG and 12-lead ECG showed a complex temporo-spatial perturbation of both depolarization and repolarization in BrS patients, prevalently localized in RV/RVOT, progressively normalizing after epicardial ablation.

Clinical Value of a Novel Three-Dimensional Echocardiography-Derived Index of Right Ventricle-Pulmonary Artery Coupling in Tricuspid Regurgitation.

BACKGROUND: Echocardiographic surrogates of right ventricle-to-pulmonary artery (RV-PA) coupling have been reported to be associated with outcomes in patients with secondary tricuspid regurgitation (STR). However, pulmonary artery systolic pressure (PASP) is difficult to estimate using echocardiography in patients with severe STR. The aim of the present study was to evaluate the predictive power of a surrogate of RV-PA coupling obtained using right ventricular (RV) volumes measured on three-dimensional echocardiography. METHODS: One hundred eight patients (mean age, 73 ± 13 years; 61% women) with moderate or severe STR were included. RESULTS: At a median follow-up of 24 months (interquartile range, 2-48 months), 72 patients (40%) had reached the composite end point of death of any cause and heart failure hospitalization. RV-PA coupling was computed as the ratio between RV forward stroke volume (SV) (i.e., RV SV - regurgitant volume) and RV end-systolic volume (ESV). RV forward SV/ESV was significantly more related to the composite end point than RV ejection fraction (area under the curve, 0.85 [95% CI, 0.78-0.93] vs 0.73 [95% CI, 0.64-0.83], respectively; P = .03). A value of 0.40 was found to best correlate with outcome. On multivariate Cox regression, RV forward SV/ESV, tricuspid annular plane systolic excursion/PASP, and RV free wall longitudinal strain/PASP were all independently associated with the occurrence of the composite end point when added to a group of parameters including STR severity (severe vs moderate), atrial fibrillation, pulmonary arterial hypertension, right atrial volume, RV end-diastolic volume, and RV free wall longitudinal strain. RV forward SV/ESV < 0.40 (HR, 3.36; 95% CI, 1.49-7.56; P < .01) carried higher related risk than RV free wall longitudinal strain/PASP < -0.42%/mm Hg (HR, 3.1; 95% CI, 1.26-7.84; P = .01) and tricuspid annular plane systolic excursion/PASP < 0.36 mm/mm Hg (HR, 2.69; 95% CI, 1.29-5.58; P = .01). RV ejection fraction did not correlate independently with prognosis when added to the same group of variables. CONCLUSIONS: RV forward SV/ESV is associated with the risk for death and heart failure hospitalization in patients with STR.

Incremental Value of Right Atrial Strain Analysis to Predict Atrial Fibrillation Recurrence After Electrical Cardioversion.

BACKGROUND: Although the assessment of left atrial (LA) mechanics has been reported to refine atrial fibrillation (AF) risk prediction, it doesn't completely predict AF recurrence. The potential added role of right atrial (RA) function in this setting is unknown. Accordingly, this study sought to evaluate the added value of RA longitudinal reservoir strain (RASr) for the prediction of AF recurrence after electrical cardioversion (ECV). METHODS: We retrospectively studied 132 consecutive patients with persistent AF who underwent elective ECV. Complete two-dimensional and speckle-tracking echocardiography analyses of LA and RA size and function were obtained in all patients before ECV. The end point was AF recurrence. RESULTS: During a 12-month follow-up, 63 patients (48%) showed AF recurrence. Both LASr and RASr were significantly lower in patients experiencing AF recurrence than in patients with persistent sinus rhythm (LASr, 10% ± 6% vs 13% ± 7%; RASr, 14% ± 10% vs 20% ± 9%, respectively; P < .001 for both). Right atrial longitudinal reservoir strain (area under the curve = 0.77; 95% CI, 0.69-0.84; P < .0001) was more strongly associated with the recurrence of AF after ECV than LASr (area under the curve = 0.69; 95% CI, 0.60-0.77; P < .0001). Kaplan-Meier curves showed that patients with both LASr ≤ 10% and RASr ≤ 15% had a significantly increased risk for AF recurrence (log-rank, P < .001). However, at multivariable Cox regression, RASr (hazard ratio, 3.26; 95% CI, 1.73-6.13; P < .001) was the only parameter independently associated with AF recurrence. Right atrial longitudinal reservoir strain was more strongly associated with the occurrence of AF relapse after ECV than LASr, and LA and RA volumes. CONCLUSION: Right atrial longitudinal reservoir strain was independently and more strongly associated than LASr with AF recurrence after elective ECV. This study highlights the importance of assessing the functional remodeling of both the RA and LA in patients with persistent AF.

Impact of severe secondary tricuspid regurgitation on rest and exercise hemodynamics of patients with heart failure and a preserved left ventricular ejection fraction.

Background: Both secondary tricuspid regurgitation (STR) and heart failure with preserved ejection fraction (HFpEF) are relevant public health problems in the elderly population, presenting with potential overlaps and sharing similar risk factors. However, the impact of severe STR on hemodynamics and cardiorespiratory adaptation to exercise in HFpEF remains to be clarified. Aim: To explore the impact of STR on exercise hemodynamics and cardiorespiratory adaptation in HFpEF. Methods: We analyzed invasive hemodynamics and gas-exchange data obtained at rest and during exercise from HFpEF patients with severe STR (HFpEF-STR), compared with 1:1 age-, sex-, and body mass index (BMI)- matched HFpEF patients with mild or no STR (HFpEF-controls). Results: Twelve HFpEF with atrial-STR (mean age 72 years, 92% females, BMI 28 Kg/m2) and 12 HFpEF-controls patients were analyzed. HFpEF-STR had higher (p < 0.01) right atrial pressure than HFpEF-controls both at rest (10 ± 1 vs. 5 ± 1 mmHg) and during exercise (23 ± 2 vs. 14 ± 2 mmHg). Despite higher pulmonary artery wedge pressure (PAWP) at rest in HFpEF-STR than in HFpEF-controls (17 ± 2 vs. 11 ± 2, p = 0.04), PAWP at peak exercise was no more different (28 ± 2 vs. 29 ± 2). Left ventricular transmural pressure and cardiac output (CO) increased less in HFpEF-STR than in HFpEF-controls (interaction p-value < 0.05). This latter was due to lower stroke volume (SV) values both at rest (48 ± 9 vs. 77 ± 9 mL, p < 0.05) and at peak exercise (54 ± 10 vs. 93 ± 10 mL, p < 0.05). Despite these differences, the two groups of patients laid on the same oxygen consumption isophlets because of the increased peripheral oxygen extraction in HFpEF-STR (p < 0.01). We found an inverse relationship between pulmonary vascular resistance and SV, both at rest and at peak exercise (R 2 = 0.12 and 0.19, respectively). Conclusions: Severe STR complicating HFpEF impairs SV and CO reserve, leading to pulmonary vascular de-recruitment and relative left heart underfilling, undermining the typical HFpEF pathophysiology.

Corrigendum: The atrial secondary tricuspid regurgitation is associated to more favorable outcome than the ventricular phenotype.

[This corrects the article DOI: 10.3389/fcvm.2022.1022755.].

An accurate and time-efficient deep learning-based system for automated segmentation and reporting of cardiac magnetic resonance-detected ischemic scar.

BACKGROUND AND OBJECTIVES: Myocardial infarction scar (MIS) assessment by cardiac magnetic resonance provides prognostic information and guides patients' clinical management. However, MIS segmentation is time-consuming and not performed routinely. This study presents a deep-learning-based computational workflow for the segmentation of left ventricular (LV) MIS, for the first time performed on state-of-the-art dark-blood late gadolinium enhancement (DB-LGE) images, and the computation of MIS transmurality and extent. METHODS: DB-LGE short-axis images of consecutive patients with myocardial infarction were acquired at 1.5T in two centres between Jan 1, 2019, and June 1, 2021. Two convolutional neural network (CNN) models based on the U-Net architecture were trained to sequentially segment the LV and MIS, by processing an incoming series of DB-LGE images. A 5-fold cross-validation was performed to assess the performance of the models. Model outputs were compared respectively with manual (LV endo- and epicardial border) and semi-automated (MIS, 4-Standard Deviation technique) ground truth to assess the accuracy of the segmentation. An automated post-processing and reporting tool was developed, computing MIS extent (expressed as relative infarcted mass) and transmurality. RESULTS: The dataset included 1355 DB-LGE short-axis images from 144 patients (MIS in 942 images). High performance (> 0.85) as measured by the Intersection over Union metric was obtained for both the LV and MIS segmentations on the training sets. The performance for both LV and MIS segmentations was 0.83 on the test sets. Compared to the 4-Standard Deviation segmentation technique, our system was five times quicker (<1 min versus 7 ± 3 min), and required minimal user interaction. CONCLUSIONS: Our solution successfully addresses different issues related to automatic MIS segmentation, including accuracy, time-effectiveness, and the automatic generation of a clinical report.

The atrial secondary tricuspid regurgitation is associated to more favorable outcome than the ventricular phenotype.

Aim: We sought to evaluate the differences in prognosis between the atrial (A-STR) and the ventricular (V-STR) phenotypes of secondary tricuspid regurgitation. Materials and methods: Consecutive patients with moderate or severe STR referred for echocardiography were enrolled. A-STR and V-STR were defined according to the last ACC/AHA guidelines criteria. The primary endpoint was the composite of all-cause death and heart failure (HF) hospitalizations. Results: A total of 211 patients were enrolled. The prevalence of A-STR in our cohort was 26%. Patients with A- STR were significantly older and with lower NYHA functional class than V-STR patients. The prevalence of severe STR was similar (28% in A-STR vs. 37% in V-STR, p = 0.291). A-STR patients had smaller tenting height (TH) (10 ± 4 mm vs. 12 ± 7 mm, p = 0.023), larger end-diastolic tricuspid annulus area (9 ± 2 cm2 vs. 7 ± 6 cm2/m2, p = 0.007), smaller right ventricular (RV) end-diastolic volumes (72 ± 27 ml/m2 vs. 92 ± 38 ml/m2; p = 0.001), and better RV longitudinal function (18 ± 7 mm vs. 16 ± 6 mm; p = 0.126 for TAPSE, and -21 ± 5% vs. -18 ± 5%; p = 0.006, for RV free-wall longitudinal strain, RVFWLS) than V-STR patients. Conversely, RV ejection fraction (RVEF, 48 ± 10% vs. 46 ± 11%, p = 0.257) and maximal right atrial volumes (64 ± 38 ml/m2 vs. 55 ± 23 ml/m2, p = 0.327) were similar between the two groups. After a median follow-up of 10 months, patients with V-STR had a 2.7-fold higher risk (HR: 2.7, 95% CI 95% = 1.3-5.7) of experiencing the combined endpoint than A-STR patients. The factors related to outcomes resulted different between the two STR phenotypes: TR-severity (HR: 5.8, CI 95% = 1, 4-25, P = 0.019) in A-STR patients; TR severity (HR 2.9, 95% CI 1.4-6.3, p = 0.005), RVEF (HR: 0.97, 95% CI 0.94-0.99, p = 0.044), and RVFWLS (HR: 0.93, 95% CI 0.85-0.98, p = 0.009) in V-STR. Conclusion: Almost one-third of patients referred to the echocardiography laboratory for significant STR have A-STR. A-STR patients had a lower incidence of the combined endpoint than V-STR patients. Moreover, while TR severity was the only independent factor associated to outcome in A-STR patients, TR severity and RV function were independently associated with outcome in V-STR patients.

Reference ranges of tricuspid annulus geometry in healthy adults using a dedicated three-dimensional echocardiography software package.

Background: Tricuspid annulus (TA) sizing is essential for planning percutaneous or surgical tricuspid procedures. According to current guidelines, TA linear dimension should be assessed using two-dimensional echocardiography (2DE). However, TA is a complex three-dimensional (3D) structure. Aim: Identify the reference values for TA geometry and dynamics and its physiological determinants using a commercially available three-dimensional echocardiography (3DE) software package dedicated to the tricuspid valve (4D AutoTVQ, GE). Methods: A total of 254 healthy volunteers (113 men, 47 ± 11 years) were evaluated using 2DE and 3DE. TA 3D area, perimeter, diameters, and sphericity index were assessed at mid-systole, early- and end-diastole. Right atrial (RA) and ventricular (RV) end-diastolic and end-systolic volumes were also measured by 3DE. Results: The feasibility of the 3DE analysis of TA was 90%. TA 3D area, perimeter, and diameters were largest at end-diastole and smallest at mid-systole. Reference values of TA at end-diastole were 9.6 ± 2.1 cm2 for the area, 11.2 ± 1.2 cm for perimeter, and 38 ± 4 mm, 31 ± 4 mm, 33 ± 4 mm, and 34 ± 5 mm for major, minor, 4-chamber and 2-chamber diameters, respectively. TA end-diastolic sphericity index was 81 ± 11%. All TA parameters were correlated with body surface area (BSA) (r from 0.42 to 0.58, p < 0.001). TA 3D area and 4-chamber diameter were significantly larger in men than in women, independent of BSA (p < 0.0001). There was no significant relationship between TA metrics with age, except for the TA minor diameter (r = -0.17, p < 0.05). When measured by 2DE in 4-chamber (29 ± 5 mm) and RV-focused (30 ± 5 mm) views, both TA diameters resulted significantly smaller than the 4-chamber (33 ± 4 mm; p < 0.0001), and the major TA diameters (38 ± 4 mm; p < 0.0001) measured by 3DE. At multivariable linear regression analysis, RA maximal volume was independently associated with both TA 3D area at mid-systole (R 2 = 0.511, p < 0.0001) and end-diastole (R 2 = 0.506, p < 0.0001), whereas BSA (R 2 = 0.526, p < 0.0001) was associated only to mid-systolic TA 3D area. Conclusions: Reference values for TA metrics should be sex-specific and indexed to BSA. 2DE underestimates actual 3DE TA dimensions. RA maximum volume was the only independent echocardiographic parameter associated with TA 3D area in healthy subjects.

Impact of correcting the 2D PISA method on the quantification of functional tricuspid regurgitation severity.

AIMS: In functional tricuspid regurgitation (FTR) patients, tricuspid leaflet tethering and relatively low jet velocity could result in proximal flow geometry distortions that lead to underestimation of TR. Application of correction factors on two-dimensional (2D) proximal isovelocity surface area (PISA) equation may increase its reliability. This study sought to evaluate the impact of the corrected 2D PISA method in quantifying FTR severity. METHODS AND RESULTS: In 102 patients with FTR, we compared both conventional and corrected 2D PISA measurements of effective regurgitant orifice area [EROA vs. corrected (EROAc)] and regurgitant volume (RegVol vs. RegVolc) with those obtained by volumetric method (VM) using three-dimensional echocardiography (3DE), as reference. Both EROAc and RegVolc were larger than EROA (0.29 ± 0.26 vs. 0.22 ± 0.21 cm2; P < 0.001) and RegVol (24.5 ± 20 vs. 18.5 ± 14.25 mL; P < 0.001), respectively. Compared with VM, both EROAc and RegVolc resulted more accurate than EROA [bias = -0.04 cm2, limits of agreement (LOA) ± 0.02 cm2 vs. bias = -0.15 cm2, LOA ± 0.31 cm2] and RegVol (bias = -3.29 mL, LOA ± 2.19 mL vs. bias = -10.9 mL, LOA ± 13.5 mL). Using EROAc and RegVolc, 37% of patients were reclassified in higher grades of FTR severity. Corrected 2D PISA method led to a higher concordance of TR severity grade with the VM method (ĸ = 0.84 vs. ĸ = 0.33 for uncorrected PISA, P < 0.001). CONCLUSION: Compared with VM by 3DE, the conventional PISA underestimated FTR severity in about 50% of patients. Correction for TV leaflets tethering angle and lower velocity of FTR jet improved 2D PISA accuracy and reclassified more than one-third of the patients.

CineECG provides a novel anatomical view on the normal atrial P-wave.

Aims: Novel CineECG computed from standard 12-lead electrocardiogram (ECG) correlated the ventricular electric activity to ventricular anatomy. CineECG was never applied to reconstruct the spatial distribution of normal atrial electric activity into an atrial anatomic model. Methods and results: From 6409 normal ECGs from PTB-XL database, we computed a median beat with fiducial points for P-and Q-onset. To determine the temporo-spatial location of atrial activity during PQ-interval, CineECG was computed on a normal 58-year-old male atrial/torso model. CineECG was projected to three major cardiac axes: posterior-anterior, right-left, base-roof, and to the standard cardiac four-chamber, left anterior oblique, and right anterior oblique (RAO) views. In 6409 normal subjects, during P-wave, CineECG moved homogeneously from right atrial roof towards left atrial base (-54 ± 14° in four-chamber view, 95 ± 24° RAO view). During terminal PQ-interval, the CineECG direction was opposite, moving towards left atrial roof (62 ± 27° in four-chamber view, 78 ± 27° RAO view). We identified the deflection point, where the atrial CineECG changes in direction. The time from P-onset to deflection point was similar to P-wave duration. Conclusion: CineECG provided a novel three-dimensional visualization of atrial electrical activity during the PQ-interval, relating atrial electrical activity to the atrial anatomy. CineECG location during P-wave and terminal PQ-interval were homogeneous within normal controls. CineECG and its deflection point may enable the early detection of atrial conduction disorders predisposing to atrial arrhythmias.

Association of outcome with left ventricular volumes and ejection fraction measured with two- and three-dimensional echocardiography in patients referred for routine, clinically indicated studies.

Objectives: We sought to analyze if left ventricular (LV) volumes and ejection fraction (EF) measured by three-dimensional echocardiography (3DE) have incremental prognostic value over measurements obtained from two-dimensional echocardiography (2DE) in patients referred to a high-volume echocardiography laboratory for routine, clinically-indicated studies. Methods: We measured LV volumes and EF using both 2DE and 3DE in 725 consecutive patients (67% men; 59 ± 18 years) with various clinical indications referred for a routine clinical study. Results: LV volumes were significantly larger, and EF was lower when measured by 3DE than 2DE. During follow-up (3.6 ± 1.2 years), 111 (15.3%) all-cause deaths and 248 (34.2%) cardiac hospitalizations occurred. Larger LV volumes and lower EF were associated with worse outcome independent of age, creatinine, hemoglobin, atrial fibrillation, and ischemic heart diseases). In stepwise Cox regression analyses, the associations of both death and cardiac hospitalization with clinical data (CD: age, creatinine, hemoglobin, atrial fibrillation, and ischemic heart disease) whose Harrel's C-index (HC) was 0.775, were augmented more by the LV volumes and EF obtained by 3DE than by 2DE parameters. The association of CD with death was not affected by LV end-diastolic volume (EDV) either measured by 2DE or 3DE. Conversely, it was incremented by 3DE LVEF (HC = 0.84, p < 0.001) more than 2DE LVEF (HC = 0.814, p < 0.001). The association of CD with the composite endpoint (HC = 0.64, p = 0.002) was augmented more by 3DE LV EDV (HC = 0.786, p < 0.001), end-systolic volume (HC = 0.801, p < 0.001), and EF (HC = 0.84, p < 0.001) than by the correspondent 2DE parameters (HC = 0.786, HC = 0.796, and 0.84, all p < 0.001) In addition, partition values for mild, moderate and severe reduction of the LVEF measured by 3DE showed a higher discriminative power than those measured by 2DE for cardiac death (Log-Rank: χ2 = 98.3 vs. χ2 = 77.1; p < 0.001). Finally, LV dilation defined according to the 3DE threshold values showed higher discriminatory power and prognostic value for death than when using 2DE reference values (3DE LVEDV: χ2 = 15.9, p < 0.001 vs. χ2 = 10.8, p = 0.001; 3DE LVESV: χ2 = 24.4, p < 0.001 vs. χ2 = 17.4, p = 0.001). Conclusion: In patients who underwent routine, clinically-indicated echocardiography, 3DE LVEF and ESV showed stronger association with outcome than the corresponding 2DE parameters.

Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy.

BACKGROUND: Vitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 (COVID-19). We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19. METHODS: We prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization. RESULTS: Severely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively, p < 0.0001 for both comparisons). 25OHD and IL-6 levels were respectively lower and higher in severely-symptomatic COVID-19 patients admitted to intensive care Unit [(ICU), 14.4 ± 8.6 ng/mL and 43.0 (19.0-56.0) pg/mL, respectively], than in those not requiring ICU admission [22.4 ± 1.4 ng/mL, p = 0.0001 and 16.0 (8.0-32.0) pg/mL, p = 0.0002, respectively]. Similar differences were found when comparing COVID-19 patients who died in hospital [13.2 ± 6.4 ng/mL and 45.0 (28.0-99.0) pg/mL] with survivors [19.3 ± 12.0 ng/mL, p = 0.035 and 21.0 (10.5-45.9) pg/mL, p = 0.018, respectively). 25OHD levels inversely correlated with: i) IL-6 levels (ρ - 0.284, p = 0.004); ii) the subsequent need of the ICU admission [relative risk, RR 0.99, 95% confidence interval (95%CI) 0.98-1.00, p = 0.011] regardless of age, gender, presence of at least 1 comorbidity among obesity, diabetes, arterial hypertension, creatinine, IL-6 and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count; iii) mortality (RR 0.97, 95%CI, 0.95-0.99, p = 0.011) regardless of age, gender, presence of diabetes, IL-6 and C-reactive protein and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count. CONCLUSION: In our COVID-19 patients, low 25OHD levels were inversely correlated with high IL-6 levels and were independent predictors of COVID-19 severity and mortality.

Role of Pharmacogenetics in Adverse Drug Reactions: An Update towards Personalized Medicine.

Adverse drug reactions (ADRs) are an important and frequent cause of morbidity and mortality. ADR can be related to a variety of drugs, including anticonvulsants, anaesthetics, antibiotics, antiretroviral, anticancer, and antiarrhythmics, and can involve every organ or apparatus. The causes of ADRs are still poorly understood due to their clinical heterogeneity and complexity. In this scenario, genetic predisposition toward ADRs is an emerging issue, not only in anticancer chemotherapy, but also in many other fields of medicine, including hemolytic anemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency, aplastic anemia, porphyria, malignant hyperthermia, epidermal tissue necrosis (Lyell's Syndrome and Stevens-Johnson Syndrome), epilepsy, thyroid diseases, diabetes, Long QT and Brugada Syndromes. The role of genetic mutations in the ADRs pathogenesis has been shown either for dose-dependent or for dose-independent reactions. In this review, we present an update of the genetic background of ADRs, with phenotypic manifestations involving blood, muscles, heart, thyroid, liver, and skin disorders. This review aims to illustrate the growing usefulness of genetics both to prevent ADRs and to optimize the safe therapeutic use of many common drugs. In this prospective, ADRs could become an untoward "stress test," leading to new diagnosis of genetic-determined diseases. Thus, the wider use of pharmacogenetic testing in the work-up of ADRs will lead to new clinical diagnosis of previously unsuspected diseases and to improved safety and efficacy of therapies. Improving the genotype-phenotype correlation through new lab techniques and implementation of artificial intelligence in the future may lead to personalized medicine, able to predict ADR and consequently to choose the appropriate compound and dosage for each patient.

Anti-Phospholipid Antibodies in COVID-19 Are Different From Those Detectable in the Anti-Phospholipid Syndrome.

Background: Critically ill patients with coronavirus disease 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy which leads to organ failure and death. Because of a prolonged activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies (aPLs) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-ß2GPI), and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies was not investigated systematically. Epitope specificity of anti-ß2GPI antibodies was not reported. Objective: To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-ß2GPI antibodies. Methods: ELISA and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic events. Results: Anti-ß2GPI IgG/IgA/IgM was the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM was detected in 5.7/6.6% by ELISA. Comparable values were found by chemiluminescence. aPS/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA. No association between thrombosis and aPL was found. Reactivity against domain 1 and 4-5 of ß2GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-ß2GPI nor with thrombosis. Conclusions: aPL show a low prevalence in COVID-19 patients and are not associated with major thrombotic events. aPL in COVID-19 patients are mainly directed against ß2GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome.

Novel CineECG Derived From Standard 12-Lead ECG Enables Right Ventricle Outflow Tract Localization of Electrical Substrate in Patients With Brugada Syndrome.

BACKGROUND: In Brugada syndrome (BrS), diagnosed in presence of a spontaneous or ajmaline-induced type-1 pattern, ventricular arrhythmias originate from the right ventricle outflow tract (RVOT). We developed a novel CineECG method, obtained by inverse electrocardiogram (ECG) from standard 12-lead ECG, to localize the electrical activity pathway in patients with BrS. METHODS: The CineECG enabled the temporospatial localization of the ECG waveforms, deriving the mean temporospatial isochrone from standard 12-lead ECG. The study sample included (1) 15 patients with spontaneous type-1 Brugada pattern, and (2) 18 patients with ajmaline-induced BrS (at baseline and after ajmaline), in whom epicardial potential duration maps were available; (3) 17 type-3 BrS pattern patients not showing type-1 BrS pattern after ajmaline (ajmaline-negative); (4) 47 normal subjects; (5) 18 patients with right bundle branch block (RBBB). According to CineECG algorithm, each ECG was classified as Normal, Brugada, RBBB, or Undetermined. RESULTS: In patients with spontaneous or ajmaline-induced BrS, CineECG localized the terminal mean temporospatial isochrone forces in the RVOT, congruent with the arrhythmogenic substrate location detected by epicardial potential duration maps. The RVOT location was never observed in normal, RBBB, or ajmaline-negative patients. In most patients with ajmaline-induced BrS (78%), the RVOT location was already evident at baseline. The CineECG classified all normal subjects and ajmaline-negative patients at baseline as Normal or Undetermined, all patients with RBBB as RBBB, whereas all patients with spontaneous and ajmaline-induced BrS as Brugada. Compared with standard 12-lead ECG, CineECG at baseline had a 100% positive predictive value and 81% negative predictive value in predicting ajmaline test results. CONCLUSIONS: In patients with spontaneous and ajmaline-induced BrS, the CineECG localized the late QRS activity in the RVOT, a phenomenon never observed in normal, RBBB, or ajmaline-negative patients. The possibility to identify the RVOT as the location of the arrhythmogenic substrate by the noninvasive CineECG, based on the standard 12-lead ECG, opens new prospective for diagnosing patients with BrS.

Anti-phospholipid antibodies in COVID-19 are different from those detectable in the anti-phospholipid syndrome.

BACKGROUND: Critically ill patients with coronavirus disease 2019 (COVID-19) have a profound hypercoagulable state and often develop coagulopathy which leads to organ failure and death. Because of a prolonged activated partial-thromboplastin time (aPTT), a relationship with anti-phospholipid antibodies (aPL) has been proposed, but results are controversial. Functional assays for aPL (i.e., lupus anticoagulant) can be influenced by concomitant anticoagulation and/or high levels of C reactive protein. The presence of anti-cardiolipin (aCL), anti-beta2-glycoprotein I (anti-ß2GPI) and anti-phosphatidylserine/prothrombin (aPS/PT) antibodies was not investigated systematically. Epitope specificity of anti-ß2GPI antibodies was not reported. OBJECTIVE: To evaluate the prevalence and the clinical association of aPL in a large cohort of COVID-19 patients, and to characterize the epitope specificity of anti-ß2GPI antibodies. METHODS: ELISA and chemiluminescence assays were used to test 122 sera of patients suffering from severe COVID-19. Of them, 16 displayed major thrombotic events. RESULTS: Anti-ß2GPI IgG/IgA/IgM were the most frequent in 15.6/6.6/9.0% of patients, while aCL IgG/IgM were detected in 5.7/6.6% by ELISA. Comparable values were found by chemiluminescence. aPS/PT IgG/IgM were detectable in 2.5 and 9.8% by ELISA. No association between thrombosis and aPL was found. Reactivity against domain 1 and 4-5 of ß2GPI was limited to 3/58 (5.2%) tested sera for each domain and did not correlate with aCL/anti-ß2GPI nor with thrombosis. CONCLUSIONS: aPL show a low prevalence in COVID-19 patients and are not associated with major thrombotic events. aPL in COVID-19 patients are mainly directed against ß2GPI but display an epitope specificity different from antibodies in antiphospholipid syndrome.

Appraisal of clinical complications after 23,827 oocyte retrievals in a large assisted reproductive technology program.

OBJECTIVE: To assess complications encountered after transvaginal oocyte retrieval procedures. DESIGN: Retrospective analysis. SETTING: University hospital, fertility center. PATIENT(S): A total of 23,827 consecutive transvaginal oocyte retrieval procedures in 12,615 patients. INTERVENTION(S): Oocyte retrieval procedures performed between June 1996 and October 2016. MAIN OUTCOME MEASURE(S): All oocyte retrieval complications. Those requiring hospital admission for at least 24 hours were considered severe. RESULT(S): A total of 96 patients (0.76 %) suffered complications, with hospital admission necessary for 71 patients (0.56 %). When calculated per retrieval, the overall complication rate was 0.4%, whereas 0.29% was the admission rate, with an average duration of hospital stay of 2.77 ± 2.5 days. A surgical procedure was necessary for 24 patients (0.1% per retrieval and 0.19% per patient). Multivariate analysis showed a significant correlation between complications and women age, body mass index (BMI), the number oocyte retrieved, and the mean time to complete oocyte retrieval. The incidence of complications was significantly higher for physicians who had performed <250 retrievals compared with those who had completed >250 retrievals (odds ratio 0.63, 95% confidence interval 0.40-0.99). CONCLUSION(S): Oocyte retrieval can be considered a safe procedure but is not without risks. The most important, identifiable, risk factors for the occurrence of complications are: [1] high number of oocytes retrieved, [2] a long duration of the procedure and mean time per oocyte retrieved, [3] inexperience of the surgeon, [4] younger patients with a lesser BMI, and [5] history of prior abdominal or pelvic surgery or pelvic inflammatory disease. CLINICAL TRIAL REGISTRATION NUMBER: NCT03282279.