Prognostic impact of left ventricular systolic dysfunction in patients with mixed aortic valve disease undergoing aortic valve replacement.

BACKGROUND: The implications of left ventricular remodeling and dysfunction before and after aortic valve replacement (AVR) for mixed aortic valve disease (MAVD) are not well understood. This study aims to evaluate the impact of AVR on left ventricular (LV) systolic function in MAVD, and determine the prognostic value of postoperative LV global longitudinal strain (LV-GLS) and LV ejection fraction (LVEF). METHODS: We retrospectively assessed 489 consecutive patients with MAVD (defined as at least moderate aortic stenosis and at least moderate aortic regurgitation) and baseline LVEF ≥50%, who underwent AVR between February 2003 and August 2018. All patients had baseline echocardiography, whereas 192 patients underwent postoperative echocardiography between 3 and 18 months after AVR. The primary endpoint was all-cause mortality. RESULTS: Mean age was 65 ± 15 years, and 65% were male. AVR in MAVD patients has a neutral effect on LV systolic function quantitated by LVEF and LV-GLS. During a median follow-up period of 5.8 years, 65 patients (34%) of 192 patients with follow-up echocardiography died. The patients with postoperative LVEF ≥50% had better survival than those with postoperative LVEF <50% (P < .001). Furthermore, among patients with postoperative LVEF ≥50%, mortality differed between patients with postoperative LV-GLS worse than -15% and those with postoperative LV-GLS better than -15% (P < .001). CONCLUSIONS: In patients with MAVD who underwent AVR, the mean postoperative LV-GLS and LVEF remain at a similar value to baseline. However, worse postoperative LV-GLS and LVEF were both independently associated with higher mortality in this population.

Left Ventricular Longitudinal Strain in Characterization and Outcome Assessment of Mixed Aortic Valve Disease Phenotypes.

OBJECTIVES: The aims of this study were to characterize the interplay between mixed aortic valve disease (MAVD) phenotypes (defined by concomitant severities of aortic stenosis and aortic regurgitation) and left ventricular global longitudinal strain (LV-GLS), and to assess the prognostic utility of LV-GLS in MAVD. BACKGROUND: Little is known about the way LV-GLS separates MAVD phenotypes and if it is associated with their outcomes. METHODS: This observational cohort study evaluated 783 consecutive adult patients with left ventricular ejection fraction ≥50% and MAVD, which was defined as coexisting with at least moderate aortic stenosis and at least moderate aortic regurgitation. We measured the conventional echocardiographic variables and average LV-GLS from apical long, 2- and 4-chamber views. The primary endpoint was all-cause mortality. RESULTS: Mean age of patients was 69 ± 15 years, and 58% were male. Mean LV-GLS was -14.7 ± 2.9%. In total, 458 patients (59%) underwent aortic valve replacement at a median period of 50 days (25th to 75th percentile range: 6 to 560 days). During a median follow-up period of 5.6 years (25th to 75th percentile range: 1.8 to 9.4 years), 391 patients (50%) died. When stratified patients into tertiles according to LV-GLS values, patients with worse LV-GLS had worse outcomes (p < 0.001). LV-GLS was independently associated with mortality (hazard ratio: 1.09; 95% confidential intervals: 1.04 to 1.14; p < 0.001), with the relationship between LV-GLS and mortality being linear. CONCLUSIONS: LV-GLS is associated with all-cause mortality. LV-GLS may be useful for risk stratification in patients with MAVD.

Long-Term Outcomes in Patients With Mixed Aortic Valve Disease and Preserved Left Ventricular Ejection Fraction.

Background Concurrent presence of aortic stenosis and aortic regurgitation is termed mixed aortic valve disease (MAVD). Although multiple articles have addressed patients with "isolated" aortic stenosis or aortic regurgitation, the natural history, impact, and outcomes of MAVD are not well defined. Here, we evaluate long-term outcomes in patients with MAVD and cardiovascular adaptations to chronic MAVD. Methods and Results This observational cohort study evaluated 862 adult patients (56.8% male) with preserved left ventricular ejection fraction and at least moderate aortic regurgitation and moderate aortic stenosis. Primary outcome was all-cause mortality. Subgroup analysis was based on treatment modality (aortic valve replacement [AVR] versus medical management). A regression analysis of longitudinal echocardiographic parameters was performed to assess the natural history of MAVD. Mean age was 68±15 years, and mean left ventricular ejection fraction was 58±5%. At 4.6 years (25th-75th percentile range, 1.0-8.7), 58.6% of patients underwent an AVR and 48.8% patients died. In both unadjusted and adjusted Cox survival analysis, AVR was associated with improved survival (hazard ratio, 0.41; 95% CI, 0.34-0.51, P<0.001). Impact of AVR persisted when stratifying the cohort by symptom status and baseline aortic valve area (log rank, P<0.001 for both) and after propensity-score matching (hazard ratio, 0.40; 95% CI, 0.32-0.50; P<0.001). In the longitudinal analysis, there were statistically significant changes over time in aortic valve peak gradient (P<0.001) and aortic valve area (P<0.001) and only mild increases in left ventricular end-diastolic (P<0.007) and -systolic (P<0.001) volumes. Conclusions MAVD confers a high risk of all-cause mortality. However, AVR significantly reduces this risk independent of aortic valve area, symptom status, and after controlling for confounding variables.

Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na⁺/K⁺-ATPase Profibrotic Signaling Pathways.

Cardiotonic steroids (CTS) are Na⁺/K⁺-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/-). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/- mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.