A novel echocardiographic risk score for light-chain amyloidosis.

Aims: The prognosis of light-chain (AL) amyloidosis, a plasma cell dyscrasia, is largely determined by the presence of cardiac involvement. Conventional staging is achieved using cardiac biomarkers (high-sensitivity troponin, N-terminal pro-beta natriuretic peptide) and free light-chain difference (Mayo staging). We sought to evaluate the role of echocardiographic parameters as prognostic markers in AL amyloidosis and examine their utility compared with conventional staging. Methods and results: Seventy-five consecutive patients with AL amyloidosis reviewed at a referral amyloid clinic who underwent comprehensive echocardiographic assessment were retrospectively identified. The evaluated echocardiographic parameters included left ventricular (LV) ejection fraction, mass, diastolic function parameters, global longitudinal strain (GLS), and left atrial (LA) volume. Mortality was assessed through a review of clinical records. During a median follow-up of 51 months, 29/75 (39%) patients died. Patients who died had a larger LA volume (47 ± 12 vs. 35 ± 10 mL/m2, P < 0.001) and a higher E/e' (18 ± 10 vs. 14 ± 6, P = 0.026). Univariate clinical and echocardiographic predictors of survival included LA volume, E/e', e', LVGLS, and Mayo stage (at significance of P < 0.1). Left atrial volume and LVGLS were significant determinants of mortality when examined using clinical cut-offs, although E/e' was not. A composite echocardiographic risk score comprising LA volume and LVGLS provided similar prognostic performance to Mayo stage [area under the curve (AUC) 0.75, 95% confidence interval (CI) 0.64-0.85 vs. AUC 0.75, 95% CI 0.65-0.858, P = 0.91]. Conclusion: Left atrial volume and LVGLS were independent predictors of mortality in AL amyloidosis. A composite echocardiographic score combining LA volume and LVGLS has similar prognostic power to Mayo stage for all-cause mortality.

Echocardiographic predictors of ventricular arrhythmias in patients with non-ischemic cardiomyopathy.

OBJECTIVE: Ventricular arrhythmias (VA) portend a poor prognosis in non-ischemic cardiomyopathy (NICM). In this meta-analysis we evaluated if left ventricular (LV) global longitudinal strain (GLS) and LV mechanical dispersion (LVMD) are associated with VA, specifically in NICM patients. METHODS: A systematic review and meta-analysis was performed to determine the predictive value of LV GLS and LVMD for VA in NICM patients. VA endpoints were a composite of sudden cardiac death, VA events (including ventricular tachycardia or ventricular fibrillation), cardiac arrest and appropriate implantable cardioverter-defibrillator (ICD) therapy. Hazard or odds ratios for univariate models were extracted for the relationship between LV GLS and LVMD with VA endpoints. RESULTS: A total of 984 patients from 6 published studies were included; 231 patients (23.5%) experienced the composite endpoint. NICM patients who experienced VA endpoints had LV GLS impairment compared to those without (weighted mean difference -1.93%; 95% confidence interval (CI) -2.77 to -1.10; p < 0.001) and LV GLS was related to VA endpoints (hazard ratio: 1.12, 95% CI 1.07-1.17, p < 0.001; odds ratio: 1.22, 95% CI 1.08-1.38, p = 0.002). Four studies reported mean LVMD (weighted mean -10.05 ms; 95% CI -28.25 to 8.14; p = 0.28), with 3 reporting risk ratios (1 reported odds ratio and 2 hazard ratios). Only odds ratio demonstrated statistical significance (hazard ratio: 0.47, 95% CI 0.01-22.25, p = 0.70; odds ratio: 1.59, 95% CI 1.14-2.22, p = 0.007). CONCLUSION: LV GLS impairment demonstrates value for predicting VA endpoints in NICM patients. Inclusion of LV GLS may be appropriate in the surveillance, screening, and clinical management of NICM patients.

Electrocardiographic Characteristics and Their Correlation with Echocardiographic Alterations in Fabry Disease.

Fabry disease (FD) is an X-linked disorder with α-galactosidase A deficiency. Males (>30 years) and females (>40 years) often present with cardiac manifestations, predominantly left ventricular hypertrophy (LVH). The aim of this study was to evaluate electrocardiographic (ECG) characteristics within FD patients to identify gender related differences, and to additionally explore the association of ECG parameters with structural and functional alterations on transthoracic echocardiography (TTE). Retrospective cross-sectional analysis of 45 FD patients with contemporaneous ECG and TTE was performed and compared to age and gender matched healthy controls. FD patients demonstrated alterations in several ECG parameters particularly in males, including prolonged P-wave duration (91 vs. 81 ms, p = 0.022), prolonged QRS duration (96 vs. 84 ms, p < 0.001), increased R-wave amplitude in lead I (8.1 vs. 5.7 mV, p = 0.047), increased Sokolow-Lyon index (25 vs. 19 mV, p = 0.002) and were more likely to meet LVH criteria (31% vs. 7%, p = 0.006). FD patients with impaired basal longitudinal strain (LS) on TTE were more likely to meet LVH criteria (41% vs. 0%, p = 0.018). Those with more advanced FD (increased LV wall thickness on TTE) were more likely to meet LVH criteria but additionally demonstrated prolonged ventricular depolarization (QRS duration 101 vs. 88 ms, p = 0.044). Therefore, alterations on ECG demonstrating delayed atrial activation, delayed ventricular depolarization and evidence of LVH were more often seen in male FD patients. Impaired basal LS, a TTE marker of early cardiac involvement, correlated with ECG abnormalities. Increased LV wall thickness on TTE, a marker of more advanced FD, was associated with more severe ECG abnormalities.

Stage-Specific L-Proline Uptake by Amino Acid Transporter Slc6a19/B0AT1 Is Required for Optimal Preimplantation Embryo Development in Mice.

L-proline (Pro) has previously been shown to support normal development of mouse embryos. Recently we have shown that Pro improves subsequent embryo development when added to fertilisation medium during in vitro fertilisation of mouse oocytes. The mechanisms by which Pro improves embryo development are still being elucidated but likely involve signalling pathways that have been observed in Pro-mediated differentiation of mouse embryonic stem cells. In this study, we show that B0AT1, a neutral amino acid transporter that accepts Pro, is expressed in mouse preimplantation embryos, along with the accessory protein ACE2. B0AT1 knockout (Slc6a19-/-) mice have decreased fertility, in terms of litter size and preimplantation embryo development in vitro. In embryos from wild-type (WT) mice, excess unlabelled Pro inhibited radiolabelled Pro uptake in oocytes and 4-8-cell stage embryos. Radiolabelled Pro uptake was reduced in 4-8-cell stage embryos, but not in oocytes, from Slc6a19-/- mice compared to those from WT mice. Other B0AT1 substrates, such as alanine and leucine, reduced uptake of Pro in WT but not in B0AT1 knockout embryos. Addition of Pro to culture medium improved embryo development. In WT embryos, Pro increased development to the cavitation stage (on day 4); whereas in B0AT1 knockout embryos Pro improved development to the 5-8-cell (day 3) and blastocyst stages (day 6) but not at cavitation (day 4), suggesting B0AT1 is the main contributor to Pro uptake on day 4 of development. Our results highlight transporter redundancy in the preimplantation embryo.

Basal Segmental Longitudinal Strain: A Marker of Subclinical Myocardial Involvement in Anderson-Fabry Disease.

BACKGROUND: Cardiac involvement in Anderson-Fabry disease (AFD) is associated with increased left ventricular (LV) wall thickness. The aim of this study was to evaluate if two-dimensional global and regional strain in patients with AFD can identify early myocardial involvement (when LV wall thickness and function are normal). Additionally, the association of altered strain with adverse cardiovascular events was evaluated. METHODS: In a retrospective cross-sectional study, 43 patients with AFD, before enzyme replacement therapy (mean age, 44 ± 12 years; 58.1% men), were compared with age- and gender-matched healthy control subjects. The mean follow-up duration among patients with AFD for major adverse cardiovascular events (MACE) was 82 months. RESULTS: LV ejection fraction was similar between groups (patients with AFD vs control subjects, 61 ± 8% vs 61 ± 6%; P = .89). However, global longitudinal strain (LS) was impaired in patients with AFD compared with control subjects (-16.5 ± 3.8% vs -20.2 ± 1.7%, P < .001), with greater impairment in patients with AFD with increased LV wall thickness (-15.4 ± 3.9% vs -18.7 ± 2.3%, P < .006). Additionally, LS was most impaired in the basal segments in patients with AFD (-14.8 ± 3.7% vs -20.3 ± 1.1%, P < .001). MACE occurred in 19 of 43 patients (four women, 15 men), and Kaplan-Meier analysis demonstrated that MACE were associated with impaired basal LS. CONCLUSIONS: In patients with AFD, altered basal LS is present even in those with normal LV wall thickness and is associated with MACE. Therefore, basal LS should be considered when screening for cardiac involvement in AFD, particularly in female patients with AFD with normal LV wall thickness.

Selected Amino Acids Promote Mouse Pre-implantation Embryo Development in a Growth Factor-Like Manner.

Groups of amino acids, and some selected amino acids, added to media used for culture of pre-implantation embryos have previously been shown to improve development in various ways including survival to the blastocyst stage, increased blastocyst cell number and improved hatching. In this study, we cultured 1-cell mouse embryos for 5 days to the hatching blastocyst stage in isosmotic medium (270 mOsm/kg) at high density (10 embryos/10 µL), where autocrine/paracrine support of development occurs, and low density (1 embryo/100 µL), where autocrine/paracrine support is minimized and development is compromised. When 400 µM L-Pro or 1 mM L-Gln was added to embryos at low density, the percentage of embryos reaching the blastocyst stage and the percentage hatching increased compared to low-density culture without these amino acids, and were now similar to those for embryos cultured at high density without amino acids. When L-Pro or L-Gln was added to embryos at high density, the percentage of embryos reaching the blastocyst stage didn't change but hatching improved. Neither embryo culture density nor the presence of these amino acids had any effect on blastocyst cell number. D-Pro and the osmolytes Gly and Betaine did not improve embryo development in low- or high-density culture indicating the mechanism was stereospecific and not osmotic, respectively. L-Pro- and L-Gln-mediated improvement in development is observed from the 5-cell stage and persists to the blastocyst stage. Molar excess of Gly, Betaine or L-Leu over L-Pro eliminated improvement in development and hatching consistent with them acting as competitive inhibitors of transporter-mediated uptake across the plasma membrane. The L-Pro effect is dependent on mTORC1 signaling (rapamycin sensitive) while that for L-Gln is not. The addition of L-Pro leads to significant nuclear translocation of p-AktS473 at the 2- and 4-cell stages and of p-ERK1/2T202/Y204 nuclear translocation at the 2-, 4-, and 8-cell stages. L-Pro improvement in embryo development involves mechanisms analogous to those seen with Pro-mediated differentiation of mouse ES cells, which is also stereoselective, dependent on transporter uptake, and activates Akt, ERK, and mTORC1 signaling pathways.

Demographic and clinical profile of cardioembolic stroke patients in Western Sydney.

BACKGROUND: Cardioembolism (CE) contributes to a large proportion of ischaemic stroke. AIMS: To evaluate the demographic and clinical profile of CE stroke in Western Sydney. METHODS: A retrospective analysis of ischaemic stroke patients presenting to Westmead Hospital (January-October 2016) was performed. Strokes were classified by TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria into different categories. Clinical and demographic data were collected on all stroke patients, and differences between CE and other stroke causes were identified. RESULTS: Two hundred and twenty-eight consecutive patients (70.9 years; 53% male) were identified. By TOAST criteria, 21 (9%) had large-artery atherosclerosis, 94 (41%) CE, 10 (5%) small-vessel disease, 2 (1%) other aetiology and 101 (44%) undetermined aetiology. A significant proportion of CE stroke patients had cardiovascular risk factors including hypertension (66%), hypercholesterolaemia (50%), diabetes (26%) and ischaemic heart disease (28%). The majority (81%) of patients with CE had atrial flutter/flutter. CE stroke, compared with other types of stroke, was more common in females (56 vs 41%, P = 0.022) and patients with CE stroke were more likely to have previous cerebral ischaemia (34 vs 21%, P = 0.026), suggesting increased recurrence in this group. Of the patients with atrial flutter/flutter (n = 56), the majority (87%) had a high CHA2 DS2 -VASC score (≥2); however, a significant proportion (55.4%) were not on anticoagulation. CONCLUSIONS: Cardioembolic stroke remains a significant burden in Western Sydney, and it is likely that a significant proportion may be preventable, as evidenced by the substantial presence of modifiable cardiovascular risk factors, and inadequate anticoagulation of patients with atrial arrhythmias.