A significant increase in cardiovascular medication use during pregnancy occurred in recent years. Only limited evidence on safety profiles is available, and little is known about the mechanisms of adverse effect on the fetus. We hypothesized that drug-induced bradycardia is the leading mechanism of developmental toxicity. Embryotoxicity was tested in ovo after administration of various doses of metoprolol, carvedilol, or ivabradine. Embryonic day (ED) 4 and 8 chick embryos were studied by video microscopy and ultrasound biomicroscopy ex ovo after intraamniotic injection of the drug for a period of 30 min. Stroke volume was calculated by the Simpson method and prolate ellipsoid formula. Significant dose-dependent mortality was achieved in embryos injected with carvedilol and ivabradine. In ED4 embryos, metoprolol, carvedilol, and ivabradine reduced the heart rate by 33%, 27%, and 55%, respectively, compared with controls (6%). In ED8 embryos this effect was more pronounced with a heart rate reduction by 71%, 54%, and 53%, respectively (controls, 36%). Cardiac output decreased in all tested groups but only proved significant in the metoprolol group in ED8 embryos. The number of β-adrenergic receptors showed a downward tendency during embryonic development. A negative chronotropic effect of metoprolol, carvedilol, and ivabradine was increasingly pronounced with embryonic maturity despite a downward trend in the number of β-adrenergic receptors. This effect was associated with reduced cardiac output in chick embryos, probably leading to premature death. Although standard doses of these drugs appear relatively safe, high doses have a potentially adverse effect on the fetus through reduced heart rate.

Background: Use of the current echocardiography-based indications for aortic regurgitation (AR) surgery might result in late valve replacement at the stage of irreversible myocardial damage. Therefore, we aimed to identify simple models combining multiple echocardiography or magnetic resonance imaging (MRI)–derived indices and natriuretic peptides (BNP [brain natriuretic peptide] or NT-proBNP [N-terminnal pro-B type natriuretic peptide]) to predict early disease decompensation in asymptomatic severe AR. Methods: This prospective and multicenter study included asymptomatic patients with severe AR, preserved left ventricular ejection fraction (>50%), and sinus rhythm. The echocardiography and MRI images were analyzed centrally in the CoreLab. The study end point was the onset of indication for aortic valve surgery as per current guidelines. Results: The derivative cohort consisted of 127 asymptomatic patients (age 45±14 years, 84% males) with 41 (32%) end points during a median follow-up of 1375 (interquartile range, 1041–1783) days. In multivariable Cox regression analysis, age, BNP, 3-dimensional vena contracta area, MRI left ventricular end-diastolic volume index, regurgitant volume, and a fraction were identified as independent predictors of end point (all P <0.05). However, a combined model including one parameter of AR assessment (MRI regurgitant volume or regurgitant fraction or 3-dimensional vena contracta area), 1 parameter of left ventricular remodeling (MRI left ventricular end-diastolic volume index or echocardiography 2-dimensional global longitudinal strain or E wave), and BNP showed significantly higher predictive accuracy (area under the curve, 0.74–0.81) than any parameter alone (area under the curve, 0.61–0.72). These findings were confirmed in the validation cohort (n=100 patients, 38 end points). Conclusions: In asymptomatic severe AR, multimodality and multiparametric model combining 2 imaging indices with natriuretic peptides, showed high accuracy to identify early disease decompensation. Further prospective studies are warranted to explore the clinical benefit of implementing these models to guide patient management. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02910349

Objective: There are no data about the prevalence of silent coronary artery disease in asymptomatic severe aortic stenosis patients with normal exercise testing. Importantly, unmasking significant coronary artery disease in patients with aortic stenosis could influence the choice/timing of treatment in these patients. Method: Exercise testing was performed on semi-supine ergobicycle. Cardiopulmonary analysis during exercise testing, echocardiography, and laboratory analysis at rest was done. Standard clinical/electrocardiography criteria were assessed for symptoms/signs of ischemia during/after exercise testing. In patients with normal exercise testing coronary angiography was performed using standard femoral/radial percutaneous approach. Coronary stenosis was considered significant if >70% of vessel diameter or 50%–70% with fractional flow reserve ≤0.8. Results: Total of 96 patients with normal exercise testing were included (67.6 years, 50.6% males). No patient had any complication or adverse event. The P _mean was 52.7 mmHg, mean indexed aortic valve area was 0.36 cm²/m² and left ventricular ejection fraction, 69.5%. 19/96 patients (19.8%) had significant coronary artery disease on coronary angiography. Multivariate logistic regression analysis revealed brain natriuretic peptide and blood glucose as independent predictors of silent coronary artery disease. Brain natriuretic peptide value of 118 pg/ml had sensitivity/specificity of 63%/73% for predicting coronary artery disease (area under the curve 0.727, P = 0.006). Conclusion: Our results are the first to show that in patients with severe aortic stenosis, normal left ventricular ejection fraction,, and normal exercise testing, significant coronary artery disease is present in as many as 1/5 patients. In such patients, further prospective studies are warranted to address the diagnostic value of brain natriuretic peptide in detecting silent coronary artery disease.

Background: Determining the value of new imaging markers to predict aortic valve (AV) surgery in asymptomatic patients with severe aortic regurgitation (AR) in a prospective, observational, multicenter study. Methods: Consecutive patients with chronic severe AR were enrolled between 2015–2018. Baseline examination included echocardiography (ECHO) with 2- and 3-dimensional (2D and 3D) vena contracta area (VCA), and magnetic resonance imaging (MRI) with regurgitant volume (RV) and fraction (RF) analyzed in CoreLab. Results: The mean follow-up was 587 days (interquartile range (IQR) 296–901) in a total of 104 patients. Twenty patients underwent AV surgery. Baseline clinical and laboratory data did not differ between surgically and medically treated patients. Surgically treated patients had larger left ventricular (LV) dimension, end-diastolic volume (all p < 0.05), and the LV ejection fraction was similar. The surgical group showed higher prevalence of severe AR (70% vs. 40%, p = 0.02). Out of all imaging markers 3D VCA, MRI-derived RV and RF were identified as the strongest independent predictors of AV surgery (all p < 0.001). Conclusions: Parameters related to LV morphology and function showed moderate accuracy to identify patients in need of early AV surgery at the early stage of the disease. 3D ECHO-derived VCA and MRI-derived RV and RF showed high accuracy and excellent sensitivity to identify patients in need of early surgery.

Reliable quantification of aortic regurgitation (AR) severity is essential for clinical management. We aimed to compare quantitative and indirect echo-Doppler indices to quantitative cardiac magnetic resonance (CMR) parameters in asymptomatic chronic severe AR. Methods and Results: We evaluated 104 consecutive patients using echocardiography and CMR. A comprehensive 2D, 3D, and Doppler echocardiography was performed. The CMR was used to quantify regurgitation fraction (RF) and volume (RV) using the phase-contrast velocity mapping technique. Concordant grading of AR severity with both techniques was observed in 77 (74%) patients. Correlation between RV and RF as assessed by echocardiography and CMR was relatively good (r_s = 0.50 for RV, r_s = 0.40 for RF, p < 0.0001). The best correlation between indirect echo-Doppler and CMR parameters was found for diastolic flow reversal (DFR) velocity in descending aorta (r_s = 0.62 for RV, r_s = 0.50 for RF, p < 0.0001) and 3D vena contracta area (VCA) (r_s = 0.48 for RV, r_s = 0.38 for RF, p < 0.0001). Using receiver operating characteristic analysis, the largest area under curve (AUC) to predict severe AR by CMR RV was observed for DFR velocity (AUC = 0.79). DFR velocity of 19.5 cm/s provided 78% sensitivity and 80% specificity. The AUC for 3D VCA to predict severe AR by CMR RV was 0.73, with optimal cut-off of 26 mm² (sensitivity 80% and specificity 66%). Conclusions: Out of the indirect echo-Doppler indices of AR severity, DFR velocity in descending aorta and 3D vena contracta area showed the best correlation with CMR-derived RV and RF in patients with chronic severe AR.