The potential of sodium-glucose cotransporter 2 inhibitors for the treatment of systemic right ventricular failure in adults with congenital heart disease

AimsGiven the compelling evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the conventional heart failure population, SGLT2i deserve exploration in systemic right ventricular (sRV) failure. The initial experience with dapagliflozin in sRV failure patients is described, with a focus on tolerability and short-term effects on clinical outcomes.Methods and resultsTen patients (70% female, median age 50 years [46.5–52]) with symptomatic sRV failure who received dapagliflozin 10 mg per day on top of optimal medical therapy between 04–2021 and 01–2023 were included. Within 4 weeks, no significant changes in blood pressure, electrolytes, or serum glucose occurred. Creatinine and estimated glomerular filtration rate (eGFR) showed a slight decline (88 ± 17 to 97 ± 23 µmol/L, p = 0.036, and 72 ± 14 vs. 66 ± 16 ml/min/1.73m2, p = 0.020, respectively). At 6 months follow-up (n = 8), median NT-proBNP decreased significantly from 736.6 [589.3–1193.3] to 531.6 [400.8–1018] ng/L (p = 0.012). Creatinine and eGFR recovered to baseline levels. There were no significant changes in echocardiographic systolic sRV or left ventricular function. New York Heart Association class improved significantly in 4 out of 8 patients (p = 0.046), who also showed an improvement in the 6-minute walk test or bicycle exercise test performance. One female patient developed an uncomplicated urinary tract infection. No patients discontinued treatment.ConclusionDapagliflozin was well-tolerated in this small cohort of sRV failure patients. While the early results on the reduction of NT-proBNP and clinical outcome parameters are encouraging, large-scale prospective studies are warranted to thoroughly evaluate the effects of SGLT2i in the growing sRV failure population

One frame and several new infinite families of Z-cyclic whist designs

AbstractIn 2001, Ge and Zhu published a frame construction which they utilized to construct a large class of Z-cyclic triplewhist designs. In this study the power and elegance of their methodology is illustrated in a rather dramatic fashion. Primarily due to the discovery of a single new frame it is possible to combine their techniques with the product theorems of Anderson, Finizio and Leonard along with a few new specific designs to obtain several new infinite classes of Z-cyclic whist designs. A sampling of the new results contained herein is as follows: (1) Z-cyclic Wh(33p+1), p a prime of the form 4t+1; (2) Z-cyclic Wh(32n+1s+1), for all n⩾1, s=5,13,17; (3) Z-cyclic Wh(32ns+1), for all n⩾1, s=35,55,91; (4) Z-cyclic Wh(32n+1s), for all n⩾1, and for all s for which there exist a Z-cyclic Wh(3s) and a homogeneous (s,4,1)-DM; and (5) Z-cyclic Wh(32ns) for all n⩾1, s=5,13. Many other results are also obtained. In particular, there exist Z-cyclic Wh(33v+1) where v is any number for which Ge and Zhu obtained Z-cyclic TWh(3v+1)

Histopathology of aortic complications in bicuspid aortic valve versus Marfan syndrome: relevance for therapy?

Patients with bicuspid aortic valve (BAV) and patients with Marfan syndrome (MFS) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common and distinct pathways of clinical relevance, we compared the histopathological substrates of aortopathy. Ascending aortic wall biopsies were divided in five groups: BAV (n = 36) and TAV (n = 23) without and with dilation and non-dilated MFS (n = 8). General histologic features, apoptosis, the expr

High burden of drug therapy in adult congenital heart disease:polypharmacy as marker of morbidity and mortality

Aims To assess medication use in adult congenital heart disease (ACHD) patients compared to the age- and sex-matched general population, identify patterns of pharmacotherapy, and analyse associations between pharmacotherapy and adverse outcomes in ACHD.Methods and results Data of 14 138 ACHD patients from the CONCOR registry [35 (24-48) years, 49% male] and age- and sex-matched referents (1:10 ratio) were extracted from the Dutch Dispensed Drug Register for the years 2006-14. Adult congenital heart disease patients had more cardiovascular and non-cardiovascular drugs than referents (median 3 vs. 1, P= 5 dispensed drug types yearly, was present in 30% of ACHD and 15% of referents {odds ratio [OR]=2.47 [95% confidence interval (CI) 2.39-2.54]}. Polypharmacy was independently associated with female sex [OR=1.92 (95% CI 1.88-1.96)], older age [for men: OR=2.3/10years (95% CI 2.2-2.4) and for women: OR=1.6/10years (95% CI 1.5-1.6); P-interactionConclusion Both cardiovascular and non-cardiovascular medication use is high in ACHD with twice as much polypharmacy compared with the matched general population. Patients with polypharmacy had a four-fold increased risk of mortality and adverse drug events. Recognition of distinct medication patterns can help identify patients at highest risk. Drug regimens need repeating evaluation to assess the appropriateness of all prescriptions. More high-quality studies are needed to improve ACHD care with more evidence-based pharmacotherapy.</p

Common genetic variants improve risk stratification after the atrial switch operation for transposition of the great arteries

Background: Clinical factors are used to estimate late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but heterogeneity in clinical course remains. We studied whether common genetic variants are associated with outcome and add value to a clinical risk score in TGA-AtrSO patients. Methods and results: This multicenter study followed 133 TGA-AtrSO patients (aged 28 [IQR 24–35] years) for 13 (IQR 9–16) years and examined the association of genome-wide single-nucleotide polymorphisms (SNPs) with a composite endpoint of symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one genome-wide significant (p 20%) risk. Stratified by the combined score, observed 5-year event-free survival was 100%, 79% and 31% for low, intermediate, and high-risk patients, respectively. Conclusions: Common genetic variants may explain some variation in the clinical course in TGA-AtrSO and improve risk stratification over clinical factors alone, especially in patients at intermediate clinical risk. These findings support the hypothesis that including genetic variants in risk assessment may be beneficial

Reduced right ventricular function on cardiovascular magnetic resonance imaging is associated with uteroplacental impairment in tetralogy of Fallot

Background: Maternal right ventricular (RV) dysfunction (measured by echocardiography) is associated with impaired uteroplacental circulation, however echocardiography has important limitations in the assessment of RV function. We therefore aimed to investigate the association of pre-pregnancy RV and left ventricular (LV) function measured by cardiovascular magnetic resonance with uteroplacental Doppler flow parameters in pregnant women with repaired Tetralogy of Fallot (ToF). Methods: Women with repaired ToF were examined, who had been enrolled in a prospective multicenter study of pregnant women with congenital heart disease. Clinical data and CMR evaluation before pregnancy were compared with uteroplacental Doppler parameters at 20 and 32 weeks gestation. In particular, pulsatility index (PI) of uterine and umbilical artery were studied. Results: We studied 31 women; mean age 30 years, operated at early age. Univariable analyses showed that reduced RV ejection fraction (RVEF; P = 0.037 and P = 0.001), higher RV end-systolic volume (P = 0.004) and higher LV end-diastolic and end-systolic volume (P = 0.001 and P = 0.003, respectively) were associated with higher uterine or umbilical artery PI. With multivariable analyses (corrected for maternal age and body mass index), reduced RVEF before pregnancy remained associated with higher umbilical artery PI at 32 weeks (P = 0.002). RVEF was lower in women with high PI compared to women with normal PI during pregnancy (44% vs. 53%, p = 0.022). LV ejection fraction was not associated with uterine or umbilical artery PI. Conclusions: Reduced RV function before pregnancy is associated with abnormal uteroplacental Doppler flow parameters. It could be postulated that reduced RV function on pre-pregnancy CMR (≤2 years) is a predisposing factor for impaired placental function in women with repaired ToF.</p

A comprehensive analysis of the intramural segment in interarterial anomalous coronary arteries using computed tomography angiography

Aims An anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS) with an interarterial course can be assessed using computed tomography angiography (CTA) for the presence of high-risk characteristics associated with sudden cardiac death. These features include a slit-like ostium, acute angle take-off, proximal luminal narrowing, and an intramural segment. To date, no robust CTA criteria exist to determine the presence of an intramural segment. We aimed to deduct new CTA parameters to distinguish an intramural course of interarterial ACAOS. Methods Twenty-five patients with an interarterial ACAOS (64% female, mean age 46 years, 88% right ACAOS) from two aca- and results demic hospitals were evaluated. Inclusion criteria were the availability of a preoperative CTA scan (0.51 mm slice thickness) and peroperative confirmation of the intramural segment. Using multiplanar reconstruction of the CTA, the distance between the lumen of the aorta and the lumen of the ACAOS [defined as ‘interluminal space’ (ILS)] was assessed at 2 mm intervals along the intramural segment. Analysis showed a mean ILS of 0.69 + 0.15 mm at 2 mm from the ostium. At the end of the intramural segment where the ACAOS becomes non-intramural, the mean ILS was significantly larger (1.27 + 0.29 mm, P, 0.001). Interobserver agreement evaluation showed good reproducibility (intraclass correlation coefficient 0.77, P, 0.001). Receiver operator characteristic analysis demonstrated that at a cut-off ILS of,0.95 mm, an intramural segment can be diagnosed with 100% sensitivity and 84% specificity. Conclusion The ILS is introduced as a novel and robust CTA parameter to identify an intramural course of interarterial ACAOS. An ILS of,0.95 mm is indicative of an intramural segment

Echocardiographic Assessment of Embryonic and Fetal Mouse Heart Development: A Focus on Haemodynamics and Morphology

Background. Heart development is a complex process, and abnormal development may result in congenital heart disease (CHD). Currently, studies on animal models mainly focus on cardiac morphology and the availability of hemodynamic data, especially of the right heart half, is limited. Here we aimed to assess the morphological and hemodynamic parameters of normal developing mouse embryos/fetuses by using a high-frequency ultrasound system. Methods. A timed breeding program was initiated with a WT mouse line (Swiss/129Sv background). All recordings were performed transabdominally, in isoflurane sedated pregnant mice, in hearts of sequential developmental stages: 12.5, 14.5, and 17.5 days after conception (n=105). Results. Along development the heart rate increased significantly from 125 ± 9.5 to 219 ± 8.3 beats per minute. Reliable flow measurements could be performed across the developing mitral and tricuspid valves and outflow tract. M-mode measurements could be obtained of all cardiac compartments. An overall increase of cardiac systolic and diastolic function with embryonic/fetal development was observed. Conclusion. High-frequency echocardiography is a promising and useful imaging modality for structural and hemodynamic analysis of embryonic/fetal mouse hearts