Timothy C. Tan

Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients treated with Anthracyclines, Taxanes and Trastuzumab

Background—Because cancer patients survive longer, the impact of cardiotoxicity associated with the use of cancer treatments escalates. The present study investigates whether early alterations of myocardial strain and blood biomarkers predict incident cardiotoxicity in patients with breast cancer during treatment with anthracyclines, taxanes, and trastuzumab. Methods and Results—Eighty-one women with newly diagnosed human epidermal growth factor receptor 2–positive breast cancer, treated with anthracyclines followed by taxanes and trastuzumab were enrolled to be evaluated every 3 months during their cancer therapy (total of 15 months) using echocardiograms and blood samples. Left ventricular ejection fraction, peak systolic longitudinal, radial, and circumferential myocardial strain were calculated. Ultrasensitive troponin I, N-terminal pro–B-type natriuretic peptide, and the interleukin family member (ST2) were also measured. Left ventricular ejection fraction decreased (64 ± 5% to 59 ± 6%; P<0.0001) over 15 months. Twenty-six patients (32%, [22%–43%]) developed cardiotoxicity as defined by the Cardiac Review and Evaluation Committee Reviewing Trastuzumab; of these patients, 5 (6%, [2%–14%]) had symptoms of heart failure. Peak systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines treatment predicted the subsequent development of cardiotoxicity; no significant associations were observed for left ventricular ejection fraction, N-terminal pro–B-type natriuretic peptide, and ST2. Longitudinal strain was <19% in all patients who later developed heart failure. Conclusions—In patients with breast cancer treated with anthracyclines, taxanes, and trastuzumab, systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines therapy are useful in the prediction of subsequent cardiotoxicity and may help guide treatment to avoid cardiac side-effects.

Ly-6Chigh Monocytes Depend on Nr4a1 to Balance both Inflammatory and Reparative Phases in the Infarcted Myocardium

Rationale: Healing after myocardial infarction involves the biphasic accumulation of inflammatory lymphocyte antigen 6C (Ly-6C)high and reparative Ly-6Clow monocytes/macrophages (Mo/M&PHgr;). According to 1 model, Mo/M&PHgr; heterogeneity in the heart originates in the blood and involves the sequential recruitment of distinct monocyte subsets that differentiate to distinct macrophages. Alternatively, heterogeneity may arise in tissue from 1 circulating subset via local macrophage differentiation and polarization. The orphan nuclear hormone receptor, nuclear receptor subfamily 4, group a, member 1 (Nr4a1), is essential to Ly-6Clow monocyte production but dispensable to Ly-6Clow macrophage differentiation; dependence on Nr4a1 can thus discriminate between systemic and local origins of macrophage heterogeneity. Objective: This study tested the role of Nr4a1 in myocardial infarction in the context of the 2 Mo/M&PHgr; accumulation scenarios. Methods and Results: We show that Ly-6Chigh monocytes infiltrate the infarcted myocardium and, unlike Ly-6Clow monocytes, differentiate to cardiac macrophages. In the early, inflammatory phase of acute myocardial ischemic injury, Ly-6Chigh monocytes accrue in response to a brief C–C chemokine ligand 2 burst. In the second, reparative phase, accumulated Ly-6Chigh monocytes give rise to reparative Ly-6Clow F4/80high macrophages that proliferate locally. In the absence of Nr4a1, Ly-6Chigh monocytes express heightened levels of C–C chemokine receptor 2 on their surface, avidly infiltrate the myocardium, and differentiate to abnormally inflammatory macrophages, which results in defective healing and compromised heart function. Conclusions: Ly-6Chigh monocytes orchestrate both inflammatory and reparative phases during myocardial infarction and depend on Nr4a1 to limit their influx and inflammatory cytokine expression.

Differential left ventricular remodelling and longitudinal function distinguishes low flow from normal-flow preserved ejection fraction low-gradient severe aortic stenosis

AIMS There is uncertainty in identifying patients with severe aortic stenosis (AS) with preserved left ventricular (LV) ejection fraction, low flow, and low gradients (LFLG). Prior studies propose that these patients demonstrate significant concentric remodelling and decreased survival, while others suggest that they have features and survival similar to moderate AS. METHODS AND RESULTS We compared the clinical characteristics, echocardiographic features, and overall survival of LFLG AS patients (n = 38) to those with normal-flow, low-gradient (NFLG) severe AS (n = 75) and moderate AS (n = 70). Low-flow, low-gradient patients had the lowest end-diastolic volume index (43 vs. 54 vs. 54 mL/m², P < 0.001), highest relative wall thickness (RWT) (60 vs. 49 vs. 48%, P < 0.001), and lowest septal mitral annular displacement (1.0 vs. 1.5 vs. 1.5 cm, P < 0.001). New York Heart Association (NYHA) class III/IV symptoms were the most frequent in the LFLG group (29 vs. 11 vs. 3%, P < 0.001). Survival at 3 years was significantly lower in LFLG compared with NFLG (P = 0.006) and moderate AS (P = 0.002), but not different between NFLG and moderate AS (P = 0.49). Higher NYHA classification (HR 1.77, 95% CI 1.22-2.57), RWT > 50% (HR 3.28, 95% CI 1.33-8.1), and septal displacement <1.1 cm (HR 3.93, 95% CI 1.96-7.82) but not low flow were independent predictors of survival in Cox proportional hazards analysis. CONCLUSION Preserved ejection fraction, LFLG AS patients exhibit marked concentric remodelling and impaired longitudinal functional-features that predict their poor long-term survival. Normal-flow, low-gradient AS patients have outcomes similar to moderate AS.

Difficulties in recruiting older people in clinical trials: An examination of barriers and solutions

Limited information exists regarding optimal methods for the recruitment and retention of older people in clinical trials. The aim of this review is to identify common barriers to the recruitment of older people in clinical trials and to propose solutions to overcome these barriers. A review of literature was performed to identify common difficulties in recruiting older people. This in combination with our experience during recruitment for a randomized control trial, have highlighted numerous barriers. Population-specific recruitment strategies, simple informed-consent processes, and effective communication between the researcher and subject are effective strategies to overcome these barriers.

Preoperative Estimates of Glomerular Filtration Rate as Predictors of Outcome after Surgery: A Systematic Review and Meta-analysis

Background:Kidney dysfunction is a strong determinant of prognosis in many settings. Methods:A systematic review and meta-analysis was undertaken to explore the relationship between estimated glomerular filtration rate (eGFR) and adverse outcomes after surgery. Cohort studies reporting the relationship between eGFR and major outcomes, including all-cause mortality, major adverse cardiovascular events, and acute kidney injury after cardiac or noncardiac surgery, were included. Results:Forty-six studies were included, of which 44 focused exclusively on cardiac and vascular surgery. Within 30 days of surgery, eGFR less than 60 ml·min·1.73 m−2 was associated with a threefold increased risk of death (multivariable adjusted relative risk [RR] 2.98; 95% confidence interval [CI] 1.95–4.96) and acute kidney injury (adjusted RR 3.13; 95% CI 2.22–4.41). An eGFR less than 60 ml·min·1.73 m−2 was associated with an increased risk of all-cause mortality (adjusted RR 1.61; 95% CI 1.38–1.87) and major adverse cardiovascular events (adjusted RR 1.49; 95% CI 1.32–1.67) during long-term follow-up. There was a nonlinear association between eGFR and the risk of early mortality such that, compared with patients having an eGFR more than 90 ml·min·1.73 m−2 the pooled RR for death at 30 days in those with an eGFR between 30 and 60 ml·min·1.73 m−2 was 1.62 (95% CI 1.43–1.80), rising to 2.85 (95% CI 2.49–3.27) in patients with an eGFR less than 30 ml·min·1.73 m−2 and 3.75 (95% CI 3.44–4.08) in those with an eGFR less than 15 ml·min·1.73 m−2. Conclusion:There is a powerful relationship between eGFR, and both short- and long-term prognosis after, predominantly cardiac and vascular, surgery.

Fetal Mammalian Heart Generates a Robust Compensatory Response to Cell Loss

Background— Heart development is tightly regulated by signaling events acting on a defined number of progenitor and differentiated cardiac cells. Although loss of function of these signaling pathways leads to congenital malformation, the consequences of cardiac progenitor cell or embryonic cardiomyocyte loss are less clear. In this study, we tested the hypothesis that embryonic mouse hearts exhibit a robust mechanism for regeneration after extensive cell loss. Methods and Results— By combining a conditional cell ablation approach with a novel blastocyst complementation strategy, we generated murine embryos that exhibit a full spectrum of cardiac progenitor cell or cardiomyocyte ablation. Remarkably, ablation of up to 60% of cardiac progenitor cells at embryonic day 7.5 was well tolerated and permitted embryo survival. Ablation of embryonic cardiomyocytes to a similar degree (50% to 60%) at embryonic day 9.0 could be fully rescued by residual myocytes with no obvious adult cardiac functional deficit. In both ablation models, an increase in cardiomyocyte proliferation rate was detected and accounted for at least some of the rapid recovery of myocardial cellularity and heart size. Conclusion— Our study defines the threshold for cell loss in the embryonic mammalian heart and reveals a robust cardiomyocyte compensatory response that sustains normal fetal development.

Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation.

RUNX2 is an essential transcription factor required for skeletal development and cartilage formation. Haploinsufficiency of RUNX2 leads to cleidocranial displaysia (CCD) a skeletal disorder characterised by gross dysgenesis of bones particularly those derived from intramembranous bone formation. A notable feature of the RUNX2 protein is the polyglutamine and polyalanine (23Q/17A) domain coded by a repeat sequence. Since none of the known mutations causing CCD characterised to date map in the glutamine repeat region, we hypothesised that Q-repeat mutations may be related to a more subtle bone phenotype. We screened subjects derived from four normal populations for Q-repeat variants. A total of 22 subjects were identified who were heterozygous for a wild type allele and a Q-repeat variant allele: (15Q, 16Q, 18Q and 30Q). Although not every subject had data for all measures, Q-repeat variants had a significant deficit in BMD with an average decrease of 0.7SD measured over 12 BMD-related parameters (p = 0.005). Femoral neck BMD was measured in all subjects (−0.6SD, p = 0.0007). The transactivation function of RUNX2 was determined for 16Q and 30Q alleles using a reporter gene assay. 16Q and 30Q alleles displayed significantly lower transactivation function compared to wild type (23Q). Our analysis has identified novel Q-repeat mutations that occur at a collective frequency of about 0.4%. These mutations significantly alter BMD and display impaired transactivation function, introducing a new class of functionally relevant RUNX2 mutants.

No association of G‐protein‐coupled receptor kinase 5 or β‐adrenergic receptor polymorphisms with Takotsubo cardiomyopathy in a large Australian cohort

Takotsubo cardiomyopathy (TC) is an increasingly recognized syndrome in which patients present with chest pain and ST changes, and are observed to have reversible LV apical ballooning in the absence of angiographically significant coronary artery stenosis. Although the pathophysiology remains unclear, the syndrome occurs almost exclusively in women, and is often triggered by stress. Recent small studies have reported association of TC with functional variants in the G‐protein‐coupled receptor kinase 5 (GRK5) gene, as well as in the β1‐adrenergic receptor (β1AR) and β2AR.

Echocardiographic parameters of left ventricular size and function as predictors of symptomatic heart failure in patients with a left ventricular ejection fraction of 50-59% treated with anthracyclines

AIMS The aim of this study was to assess whether baseline echocardiographic measures of left ventricular (LV) size and function predict the development of symptomatic heart failure or cardiac death (major adverse cardiac events, MACE) in patients treated with anthracyclines who have a pre-chemotherapy left ventricular ejection fraction (LVEF) between 50 and 59%. METHODS AND RESULTS Patients with an LVEF between 50 and 59% before anthracyclines were selected. In these patients, LV volumes, LVEF, and peak longitudinal strain (GLS) were measured. Individuals were followed for MACE and all-cause mortality over a median of 659 days (range: 3-3704 days). Of 2234 patients undergoing echocardiography for pre-anthracycline assessment, 158 (7%) had a resting ejection fraction of 50-59%. Their average LV end-diastolic volume (LVEDV) was 101 ± 22 mL, LVEF was 54 ± 3%, and global longitudinal strain (GLS) was -17.7 ± 2.6%. Twelve patients experienced a MACE (congestive heart failure) at a median of 173 days (range: 15-530). Age, diabetes, previous coronary artery disease, LVEDV, indexed LVEDV, LVESV, indexed LVESV, and GLS were all predictive of MACE (P = 0.012, 0.039, 0.0029, 0.012, and 0.0065 for LVEDV, LVEDVI, LVESV, LVESVI, and GLS, respectively). Indexed LVEDV and GLS remained predictive of MACE when adjusted for age. Age and GLS were also predictive of overall mortality (P < 0.0001 and 0.0105, respectively). CONCLUSION In patients treated with anthracyclines with an LVEF of 50-59%, both baseline EDV and GLS predict the occurrence of MACE. These parameters may help target patients who could benefit from closer cardiac surveillance and earlier initiation of cardioprotective medical therapy.

The effect of bariatric surgery on echocardiographic indices: a review of the literature

Obesity is the new epidemic and is associated with an increased risk of diastolic and systolic heart failure. Effective treatment options with drastic results such as bariatric surgery have raised interest in the possible reversal of some of the cardiovascular sequelae. Many studies have assessed individually the effect of weight loss on specific echocardiographic indices, mostly employing nonhomogeneous groups. The purpose of this narrative review is to summarise the effect of bariatric surgery on echocardiographic indices of biventricular function and to help in the understanding of the expected echocardiographic changes in bariatric patients after weight‐loss surgery