Carvedilol and Cardiac Biomarkers in Dialysis Patients: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND/AIMS: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. METHODS: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. RESULTS: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. CONCLUSIONS: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.

A randomized double-blind trial of an interventional device treatment of functional mitral regurgitation in patients with symptomatic congestive heart failure-Trial design of the REDUCE FMR study.

The Carillon Mitral Contour System has been studied in 3 nonrandomized trials in patients with symptomatic congestive heart failure and functional mitral regurgitation. The REDUCE FMR study is a uniquely designed, double-blind trial evaluating the impact of the Carillon device on reducing regurgitant volume, as well as assessing the safety and clinical efficacy of this device. Carillon is a coronary sinus-based indirect annuloplasty device. Eligible patients undergo an invasive venogram to assess coronary sinus vein suitability for the Carillon device. If the venous dimensions are suitable, they are randomized on a 3:1 basis to receive a device or not. Patients and assessors are blinded to the treatment assignment. The primary end point is the difference in regurgitant volume at 1 year between the implanted and nonimplanted groups. Other comparisons include clinical parameters such as heart failure hospitalizations, 6-minute walk test, Kansas City Cardiomyopathy Questionnaire (KCCQ), and other echocardiographic parameters. An exercise echo substudy will also be included.

Myocardial strain assessment by cine cardiac magnetic resonance imaging using non-rigid registration.

AIMS: To evaluate a novel post-processing method for assessment of longitudinal mid-myocardial strain in standard cine cardiac magnetic resonance (CMR) imaging sequences. METHODS AND RESULTS: Cine CMR imaging and tagged cardiac magnetic resonance imaging (TMRI) were performed in 15 patients with acute myocardial infarction (AMI) and 15 healthy volunteers served as control group. A second group of 37 post-AMI patients underwent both cine CMR and late gadolinium enhancement (LGE) CMR exams. Speckle tracking echocardiography (STE) was performed in 36 of these patients. Cine CMR, TMRI and STE were analyzed to obtain longitudinal strain. LGE-CMR datasets were analyzed to evaluate scar extent. Comparison of peak systolic strain (PSS) measured from CMR and TMRI yielded a strong correlation (r=0.86, p<0.001). PSS measured from CMR and STE correlated well (r=0.75, p<0.001). A cutoff longitudinal PSS value of -13.14% differentiated non-infarction from any infarcted myocardium, with a sensitivity of 93% and a specificity of 89% (area under curve (AUC) 0.95). PSS value of -9.39% differentiated non-transmural from transmural infarcted myocardium, with a sensitivity of 75% and a specificity of 67% (AUC 0.78). CONCLUSION: The present study showed a novel off-line post-processing method for segmental longitudinal strain analysis in mid-myocardium layer based on cine CMR data. The method was found to be highly correlated with strain measurements obtained by TMRI and STE. This tool allows accurate discrimination between different transmurality states of myocardial infarction.

Association between left ventricular global longitudinal strain, health-related quality of life and functional capacity in chronic kidney disease patients with preserved ejection fraction.

AIM: Patients with chronic kidney disease (CKD) have a significant burden of dyspnoea and fatigue in spite having normal left ventricular (LV) ejection fraction (EF). Global longitudinal strain (GLS) can detect subtle changes in LV function. This study aimed to evaluate the relationship between LV function, functional capacity and quality of life (QOL) in CKD patients with preserved EF. METHODS: A cross-sectional study of patients with stage 3/4 CKD (n = 108). Clinical characteristics, biochemical data, functional capacity (6-min walk test (6MWT), timed up and go (TUG) test) and QOL (short form-12 (SF-12v2™) ) were measured. Echocardiogram was used to assess GLS, EF and diastolic function (E/A, e' and E/e'). RESULTS: The mean age was 58.1 ± 9.9 years, 55.6% were men, estimated glomerular filtration rate was 44.8 ± 10.6 mL/min/1.73 m(2), GLS was -18.5 ± 3.6% and 19.4% had impaired GLS (>-16%). Patients with impaired GLS had a significantly shorter 6MWT and slower TUG test compared with patients with preserved GLS. Bivariate analysis showed GLS and E/e' correlated with distance walked in 6MWT (GLS (r = -0.24, P = 0.02); E/e'(r = -0.38, P = 0.002) ). Following adjustment for potential confounders, GLS remained independently associated with 6MWT (model R(2) = 0.37, P < 0.001). Mean physical component summary scores (PCS) and mental component summary scores (MCS) were 43.0 ± 10.2 and 50.9 ± 9.5. There was no cardiac parameter that was independently associated with PCS. However women, lower systolic blood pressure and GLS was associated with lower MCS (model R(2) = 0.30, P < 0.001). CONCLUSION: GLS was associated with measures of functional capacity and QOL in CKD patients with preserved EF.

Association of Exercise Intolerance in Type 2 Diabetes With Skeletal Muscle Blood Flow Reserve.

OBJECTIVES: This study sought to investigate the association of exercise intolerance in type 2 diabetes (T2DM) with skeletal muscle capillary blood flow (CBF) reserve. BACKGROUND: Exercise intolerance in T2DM strongly predicts adverse prognosis, but associations with muscle blood flow independent of cardiac dysfunction are undefined. METHODS: In 134 T2DM patients without cardiovascular disease, left ventricular function and contrast-enhanced ultrasound of the quadriceps (for CBF; i.e., product of capillary blood volume and velocity) were assessed at rest and immediately following treadmill exercise for peak oxygen uptake (Vo2peak). Left ventricular systolic and diastolic functional reserve indexes were derived from changes in systolic and early diastolic color tissue Doppler velocities. Cardiac index reserve and its constituents (stroke volume and chronotropic indexes) and left ventricular filling pressure (ratio of early diastolic mitral inflow and annular velocities) were also measured. RESULTS: Vo2peak correlated with muscle CBF reserve (ß = 0.16, p = 0.005) independent of cardiac index reserve and clinical covariates. This was explained by higher muscle capillary blood velocity reserve (ß = 0.18, p = 0.002), rather than blood volume reserve (p > 0.10) in patients with higher Vo2peak. A concurrent association of Vo2peak with cardiac index reserve (ß = 0.20, p < 0.001) appeared to reflect chronotropic index (ß = 0.15, p = 0.012) rather than stroke volume index reserve (p > 0.10), although the systolic functional reserve index was also identified as an independent correlate (ß = 0.16, p = 0.028). No associations of Vo2peak with diastolic functional reserve were identified (p > 0.10). CONCLUSIONS: Vo2peak is associated with muscle CBF reserve in T2DM, independent of parallel associations with cardiac functional reserve. This is consistent with a multifactorial basis for exercise intolerance in T2DM.

Left ventricular global longitudinal strain is associated with cardiovascular risk factors and arterial stiffness in chronic kidney disease.

BACKGROUND: Global longitudinal strain (GLS) has emerged as a superior method for detecting left ventricular (LV) systolic dysfunction compared to ejection fraction (EF) on the basis that it is less operator dependent and more reproducible. The 2-dimensional strain (2DS) method is easily measured and integrated into a standard echocardiogram. This study aimed to determine the relationship between GLS and traditional and chronic kidney disease (CKD)-related risk factors of cardiovascular disease (CVD) in patients with CKD. METHODS: A cross sectional study of patients with moderate CKD stages 3 and 4 (n = 136). Clinical characteristics, anthropometric, biochemical data including markers of inflammation [C-reactive protein (CRP)], uremic toxins [indoxyl sulphate (IS), p-cresyl sulphate (PCS)], and arterial stiffness [pulse wave velocity (PWV)] were measured. Inducible ischemia was detected using exercise stress echocardiogram. GLS was determined from 3 standard apical views using 2-dimensional speckle tracking and EF was measured using Simpson's rule. Associations between GLS and traditional and CKD-related risk factors were explored using multivariate models. RESULTS: The study population parameters included: age 59.4 ± 9.8 years, 58 % male, estimated glomerular filtration rate (eGFR) 44.4 ± 10.1 ml/min/1.73 m(2), GLS -18.3 ± 3.6 % and EF 65.8 % ± 7.8 %. This study demonstrated that GLS correlated with diabetes (r = 0.21, p = 0.01), history of heart failure (r = 0.20, p = 0.01), free IS (r = 0.24, p = 0.005) free PCS (r = 0.23, p = 0.007), body mass index (BMI) (r = 0.28, p < 0.001), and PWV (r = 0.24, p = 0.009). Following adjustment for demographic, baseline co-morbidities and laboratory parameters, GLS was independently associated with free IS, BMI and arterial stiffness (R(2) for model = .30, p < 0.0001). CONCLUSIONS: In the CKD cohort, LV systolic function assessed using GLS was associated with uremic toxins, obesity and arterial stiffness.

Subclinical LV dysfunction and 10-year outcomes in type 2 diabetes mellitus.

OBJECTIVE: New imaging techniques have permitted the detection of subclinical LV dysfunction (LVD) in up to half of patients with type 2 diabetes mellitus (DM) with a normal EF. However, the connection between early LVD and prognosis is unclear. This study aimed to define the long-term outcome of LVD associated with type 2 DM. METHODS: In this prospective cohort study, 230 asymptomatic patients with type 2 DM underwent measurement of global longitudinal 2D strain (GLS) for detection of LVD and were followed for up to 10 years. All subjects had normal EF (≥50%) and no evidence of coronary artery disease at recruitment. Outcome data were obtained through centralised state-wide death and hospital admission registries. The primary endpoint was all-cause mortality and hospitalisation. RESULTS: On study entry, almost half (45%) of the cohort had evidence of LVD as detected by GLS. Over a median follow-up of 7.4±2.6 years (range 0.6-9.7 years), 68 patients (30%) met the primary endpoint (LVD: 37%; normal LV function: 24%). GLS was independently associated with the primary endpoint (HR=1.10; p=0.04), as was systolic blood pressure (HR=1.02; p<0.001) and levels of glycosylated haemoglobin (HR=1.28; p=0.011). Patients with LVD had significantly worse outcome than those without (χ(2)=4.73; p=0.030). CONCLUSIONS: Subclinical LVD is common in asymptomatic patients with type 2 DM, is readily detectable by GLS imaging and is independently associated with adverse outcome. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry (ACTRN12612001178831).

Left Ventricular Global Longitudinal Strain (GLS) Is a Superior Predictor of All-Cause and Cardiovascular Mortality When Compared to Ejection Fraction in Advanced Chronic Kidney Disease.

BACKGROUND: Echocardiographic global longitudinal strain (GLS) is increasingly recognised as a more effective technique than conventional ejection fraction (EF) in detecting subtle changes in left ventricular (LV) function. This study investigated the prognostic value of GLS over EF in patients with advanced Chronic Kidney Disease (CKD). METHODS: The study included 183 patients (57% male, 63% on dialysis) with CKD stage 4, 5 and 5Dialysis (D). 112 (61%) of patients died in a follow up of 7.8 ± 4.4 years and 41% of deaths were due to cardiovascular (CV) disease. GLS was calculated using 2-dimensional speckle tracking and EF was measured using Simpson's biplane method. Cox proportional hazard models were used to assess the association of measures of LV function and all- cause and CV mortality. RESULTS: The mean GLS at baseline was -13.6 ± 4.3% and EF was 45 ± 11%. GLS was a significant predictor of all-cause [Hazard Ratio (HR) 1.09 95%; Confidence Interval (CI) 1.02-1.16; p = 0.01] and CV mortality (HR 1.16 95%; CI 1.04-1.30; p = 0.008) following adjustment for relevant clinical variables including LV mass index (LVMI) and EF. GLS also had greater predictive power for both all- cause and CV mortality compared to EF. Impaired GLS (>-16%) was associated with a 5.6-fold increased unadjusted risk of CV mortality in patients with preserved EF. CONCLUSIONS: In this cohort of patients with advanced CKD, GLS is a more sensitive predictor of overall and CV mortality compared to EF. Studies of larger populations in CKD are required to confirm that GLS provides additive prognostic value in patients with preserved EF.

A six-month exercise intervention in subclinical diabetic heart disease: effects on exercise capacity, autonomic and myocardial function.

OBJECTIVE: Autonomic dysfunction may contribute to the etiology and exercise intolerance of subclinical diabetic heart disease. This study sought the efficacy of exercise training for improvement of peak oxygen uptake (VO2(peak)) and cardiac autonomic function in type 2 diabetic patients with non-ischemic subclinical left-ventricular (LV) dysfunction. MATERIALS/METHODS: Forty-nine type 2 diabetic patients with early diastolic tissue Doppler velocity >1 standard deviation below the age-based mean entered an exercise intervention (n=24) or usual care (n=25) for 6-months (controlled, pre-/post- design). Co-primary endpoints were treadmill VO2(peak) and 5-min heart-rate variability (by the coefficient of variation of normal RR intervals [CVNN]). Autonomic function was additionally assessed by resting heart-rate (for sympathovagal balance estimation), baroreflex sensitivity, cardiac reflexes, and exercise/recovery heart-rate profiles. Echocardiography was performed for LV function (systolic/diastolic tissue velocities, myocardial deformation) and myocardial fibrosis (calibrated integrated backscatter). RESULTS: VO2(peak) increased by 11% during the exercise intervention (p=0.001 vs. -1% in controls), but CVNN did not change (p=0.23). Reduction of resting heart-rate in the intervention group (p<0.05) was associated with an improvement in the secondary endpoint of heart-rate variability total spectral power (p<0.05). However, baroreflex sensitivity, cardiac reflexes, and exercise/recovery heart-rate profiles showed no significant benefit. No effects on LV function were observed despite favorable reduction of calibrated integrated backscatter in the intervention group (p<0.05). CONCLUSIONS: The exercise intolerance of subclinical diabetic heart disease was amenable to improvement by exercise training. Despite a reduction in resting heart-rate and potential attenuation of myocardial fibrosis, no other cardiac autonomic or LV functional adaptations were detected.

The association between left ventricular global longitudinal strain, renal impairment and all-cause mortality.

BACKGROUND: Left ventricular (LV) systolic dysfunction is an important predictor of cardiovascular death. Global longitudinal strain (GLS) is a widely available echocardiographic technique proven to be more sensitive than conventional ejection fraction (EF) in detecting subtle changes in LV function. However, the prognostic value of GLS in patients with chronic kidney disease (CKD) is unknown. METHODS: We studied 447 patients from a single center who were stratified according to estimated glomerular filtration rate (eGFR). GLS was calculated using two-dimensional speckle tracking and EF was measured using Simpson's biplane. Cox proportional hazard model was used to identify independent predictors of survival and measures of discrimination and reclassification were used to assess the predictive value of GLS. Multivariable regression models were used to evaluate clinical and laboratory factors associated with GLS. RESULTS: The mean EF was 58 ± 11% and GLS was -16.6 ± 4.2%. eGFR correlated negatively with GLS (r = -0.14, P = 0.004). Factors that were independently associated with GLS include gender, previous myocardial infarction, eGFR and phosphate (R(2) = 0.16, P < 0.001). Sixty-four patients died in a follow-up of 5.2 ± 1.4 years. GLS remained a significant predictor of all-cause mortality [hazard ratio (HR) 1.08, 95% confidence interval (CI) 1.01-1.15] following adjustment for age, diabetes mellitus, hypertension, eGFR and left ventricular mass index (LVMI). The strength of association between demographic data, eGFR, LVMI and mortality increased following addition of GLS [c-statistic 0.68 (95% CI 0.61-0.74) to 0.71 (95% CI 0.64-0.77), P = 0.04]. Addition of GLS also demonstrated a 21% net reclassification improvement in risk prediction for all-cause mortality over clinical factors. CONCLUSIONS: GLS is an important predictor of all-cause mortality in CKD patients. Traditional and non-traditional risk factors such as phosphate are important determinants of GLS. Strain assessment in CKD patients may provide greater cardiovascular risk stratification.

Hemodynamic benefit of rest and exercise optimization of cardiac resynchronization therapy.

The optimal method of cardiac resynchronization therapy (CRT) optimization is as yet unknown. We sought to investigate the responses of optimization at rest and on exercise. This 2 stage study involved 59 patients (age 65 ± 10, 75% male), who had all recently undergone successful CRT implantation. In the first stage, the 6-month response was compared between 30 individuals who underwent resting echocardiographic optimization of CRT [atrioventricular (AV delay) plus ventriculo-ventricular delays (VV delay)], compared with the 29 who did not. In the second stage, a subset of 37 patients from the original cohort were randomized (double-blind) to either resting echocardiographic optimization (n = 20) or exercise echocardiographic optimization (n = 17) and followed for a further 6 months. Clinical and echocardiographic data were collected at each stage. Patients undergoing rest optimization demonstrated improvement in almost all variables and significantly in B-type natriuretic peptide (BNP) in contrast to those without optimization. In a linear regression model, the only significant predictor of BNP change was whether an individual underwent resting optimization or not (ß = 0.38, P = 0.04). In those undergoing resting optimization, the degree of change in AV delay was correlated with improvement in left ventricle (LV) end-diastolic volume (r(2)  = 0.33, P < 0.01). Optimization on exercise was associated with a significant decrease in 6-minute walk test compared to those randomized to rest optimization possibly due to inducing nonoptimization at rest. In conclusion, echocardiographic optimization of CRT at rest is superior to no optimization or optimization on exercise. Patients with the greatest change in AV delay to reach optimal may undergo greater LV remodeling.

Association of outcome with left ventricular parameters measured by two-dimensional and three-dimensional echocardiography in patients at high cardiovascular risk.

BACKGROUND: Left ventricular (LV) ejection fraction (EF) measured by two-dimensional echocardiographic (2DE) imaging is an important correlate of survival. Real-time three-dimensional echocardiographic (3DE) imaging has addressed some of the limitations of 2DE imaging. The aim of this study was to determine whether 3DE imaging is more predictive of outcomes than 2DE imaging. METHODS: A total of 529 patients undergoing LV assessment with 2DE and 3DE imaging in 2003 and 2004 at a tertiary referral cardiac center were studied. Patients had a high frequency of cardiovascular risk factors. Images were gathered over four cardiac cycles using a matrix-array transducer, with measurements performed offline. Follow-up (all-cause mortality or cardiac hospitalization) was obtained over 6.6 ± 3.4 years in 455 of 486 patients with images suitable for measurement (94%). RESULTS: There were 194 events (43%), including 75 deaths (16.4%). Larger LV volumes and lower EF were associated with worse outcomes independent of age, heart failure, or end-stage renal disease. In stepwise Cox regression analyses, the associations of cardiac hospitalization and survival with clinical variables (age, chronic kidney disease, and heart failure) were augmented by 3DE EF and end-systolic volume more than by 2DE parameters. The incremental model χ(2) value with 3DE EF was 14.67 (P < .001), compared with 9.72 (P = .002) for 2DE EF. Similarly, in Cox regression analyses of mortality, the effects of clinical variables (age, advanced renal disease, and heart failure) were augmented more by 3DE EF (incremental χ(2) = 14.04, P < .0001) than 2DE EF (incremental χ(2) = 5.13, P = .024). CONCLUSIONS: In this outcome study, 3DE EF and volumes showed stronger associations with outcomes than those derived from 2DE imaging.

Uremic toxin development in living kidney donors: a longitudinal study.

BACKGROUND: Emerging evidence suggests that uremic toxins, in particular indoxyl sulfate (IS) and p-cresyl sulfate (PCS), may be involved in the pathogenesis of cardiovascular disease. Despite a significant increase in IS and PCS in patients with established kidney damage, the effect of a nephrectomy in non-chronic kidney disease patients is not yet known. METHODS: Forty-two living kidney donors (Caucasian; 76% female [n=32]; 53 ± 10 years) were enrolled in an observational cohort study and followed up annually for 2 years (before nephrectomy, 1 and 2 years after nephrectomy). At each time point, patients underwent measurements of serum total and free IS and PCS (using ultrahigh-performance liquid chromatography), carotid intima-media thickness (a measure of arterial stiffness), brachial artery reactivity (both flow-mediated dilatation and sublingual glycerol trinitrate, markers of endothelial dysfunction), kidney function by Chronic Kidney Disease Epidemiology Collaboration creatinine-cystatin C, and urate and high-sensitivity C-reactive protein using standard laboratory techniques. RESULTS: Kidney function decreased by 30% after nephrectomy (absolute change estimated glomerular filtration rate 28 ± 6.9 and 27 ± 7.6 mL/min/1.73 m at 1 and 2 years, respectively), and the concentration of toxin levels increased by 44% to 100%, which remained elevated at 2 years after nephrectomy (all P<0.001). Both toxins were associated with carotid intima-media thickness, brachial artery reactivity-glycerol trinitrate, serum urate, and C-reactive protein levels (all P<0.03). Further, IS and urate were found to be independent predictors of change in kidney function, from baseline at 2 years after nephrectomy (both P<0.03). CONCLUSION: This study demonstrated significant and sustained increases in nephrovascular toxins, IS and PCS, after nephrectomy. Levels of both toxins were associated with clinically relevant markers of cardiovascular and renal risk, warranting further research in this area.

Use of speckle strain to assess left ventricular responses to cardiotoxic chemotherapy and cardioprotection.

AIMS: The variability of ejection fraction (EF) poses a problem in the assessment of left ventricular (LV) function in patients receiving potentially cardiotoxic chemotherapy. We sought to use global longitudinal strain (GLS) to compare LV responses to various cardiotoxic chemotherapy regimens and to examine the response to cardioprotection with beta-blockers (BB) in patients showing subclinical myocardial damage. METHODS AND RESULTS: We studied 159 patients (49 ± 14 year, 127 women) receiving anthracycline (group A, n = 53, 46 ± 17 year), trastuzumab (group T, n = 61, 53 ± 12 year), or trastuzumab after anthracyclines (group AT, n = 45, 46 ± 9 year). LV indices [ejection fraction (EF), mitral annular systolic velocity, and GLS] were measured at baseline and follow-up (7 ± 7 months). Patients who decreased GLS by ≥11% were followed for another 6 months; initiation of BB was at the discretion of the clinician. Anthracycline dose was similar between group A and group AT (213 ± 118 vs. 216 ± 47 mg/m(2), P = 0.85). Although ΔEF was similar among the groups, attenuation of GLS was the greatest in group AT (group A, 0.7 ± 2.8% shortening; T, 1.1 ± 2.7%; and AT, 2.0 ± 2.3%; P = 0.003, after adjustment). Of 52 patients who decreased GLS by ≥-11%, 24 were treated with BB and 28 were not. GLS improved in BB groups (from -17.6 ± 2.3 to -19.8 ± 2.6%, P < 0.001) but not in non-BB groups (from -18.0 ± 2.0 to -19.0 ± 3.0%, P = 0.08). Effects of BB were similar with all regimens. CONCLUSIONS: GLS is an effective parameter for identifying systolic dysfunction (which appears worst with combined anthracycline and trastuzumab therapy) and responds to cardioprotection in patients administered beta-blockers.

Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity.

BACKGROUND: Assessment of left ventricular systolic function is necessary during trastuzumab-based chemotherapy because of potential cardiotoxicity. Deformation indices have been proposed as an adjunct to clinical risk factors and ejection fraction (EF), but the optimal parameter and optimal cutoffs are undefined. The aim of this study was to determine the best means of early detection of subsequent reduction of EF in patients with breast cancer treated with trastuzumab. METHODS: Eighty-one consecutive women (mean age, 50 ± 11 years) receiving trastuzumab were prospectively studied, 37 of whom received concurrent anthracyclines. Conventional echocardiographic indices (mitral annular systolic [s'] and diastolic [e'] velocities) and myocardial deformation indices (global longitudinal peak systolic strain [GLS], global longitudinal peak systolic strain rate [GLSR-S], and global longitudinal early diastolic strain rate [GLSR-E]) were measured at baseline and at 6 and 12 months. Cardiotoxicity was defined as a >10% decline as a percentage of baseline EF in 12 months. RESULTS: In the 24 patients (30%) who later developed cardiotoxicity, myocardial deformation indices decreased at 6 months (GLS, P < .001; GLSR-S, P = .009; GLSR-E, P = .002 vs baseline), but e' was unchanged. The strongest predictor of cardiotoxicity was ΔGLS (area under the curve, 0.84); an 11% reduction (95% confidence interval, 8.3%-14.6%) was the optimal cutoff, with sensitivity of 65% and specificity of 94%. In sequential models, the clinical model (χ(2) = 10.2) was improved by GLSR-S (χ(2) = 14.7, P = .03) and even more so by GLSR-E (χ(2) = 18.0, P = .005) or GLS (χ(2) = 21.3, P = .0008). Discrimination improvement by adding GLS was confirmed by an integrated discrimination improvement of 18.6% (95% confidence interval, 8.6%-28.6%; P = .0003). A net 29% of the patients without events were reclassified into lower risk categories, and a net 48% of the patients with events were reclassified into higher risk categories, resulting in a total continuous net reclassification improvement (>0) of 0.77 (95% confidence interval, 0.33-1.22; P = .036). CONCLUSIONS: GLS is an independent early predictor of later reductions in EF, incremental to usual predictors in patients at risk for trastuzumab-induced cardiotoxicity.

Heart failure, ventricular dysfunction and risk factor prevalence in Australian Aboriginal peoples: the Heart of the Heart Study.

BACKGROUND: Limited strategies have been developed to evaluate and address the alarming discrepancy in early mortality between Indigenous and non-Indigenous populations. OBJECTIVE: To assess heart failure (HF), HF risk factors and document cardiac characteristics in an Australian Aboriginal population. DESIGN, SETTING, PARTICIPANTS: Adults were enrolled across six Aboriginal communities in Central Australia. They undertook comprehensive cardiovascular assessments, including echocardiography, to determine HF status, asymptomatic ventricular dysfunction and underlying risk factor profile. RESULTS: Of 436 participants (mean age 44±14 years; 64% women) enrolled, 5.3% (95% CI 3.2% to 7.5%) were diagnosed with HF, only 35% of whom had a pre-existing HF diagnosis. Asymptomatic left ventricular dysfunction (ALVD) was seen in 13% (95% CI 9.4% to 15.7%) of the population. Estimates of HF risk factor prevalence were as follows: body mass index (BMI) ≥30 kg/m(2) 42%, hypertension 41%, diabetes mellitus 40%, coronary artery disease (CAD) 7% and history of acute rheumatic fever or rheumatic heart disease 7%. In logistic regression analysis (after adjustment for age and gender), HF was associated with CAD (OR=9.6, p<0.001), diabetes (OR=5.4, p=0.002), hypertension (OR=4.8, p=0.006), BMI ≥30 kg/m(2) (OR=2.9, p=0.02), acute rheumatic fever or rheumatic heart disease (OR=5.6, p=0.001) and B-type natriuretic peptide (OR=1.02, p<0.001). CONCLUSION: The burden of HF, ALVD and risk factors in this population was extremely high. This study highlights potentially modifiable targets on which to focus resources and screening strategies to prevent HF in this high-risk Indigenous population.

Multimodality vascular imaging in CKD: divergence of risk between measured parameters.

BACKGROUND: High cardiovascular risk in chronic kidney disease (CKD) patients appears only partly attributable to atherosclerosis, with much of the remaining risk being ascribed to other vasculature abnormalities, including endothelial dysfunction, arterial stiffness and vascular calcification (VC). To date, these factors have been primarily studied in isolation or in dialysis patients. This study performed a global vascular assessment in moderate CKD and assessed the relationships with both traditional and novel risk factors. METHODS: This was a prospective cross-sectional analysis of 120 patients (age 60 ± 10 years; estimated glomerular filtration rate 25-60 mL/min/1.73m(2)). Demographic, clinical and biochemical characterization was performed. VC was characterized by lateral lumbar radiograph; arterial stiffness by aortic pulse-wave velocity (PWV); atheroma burden by carotid intima-media thickness (cIMT) and endothelial function by flow-mediated dilation (FMD) of the brachial artery. RESULTS: VC was highly prevalent (74%), and FMD generally poor (FMDΔ 3.3 ± 3.3%). There were significant correlations between all vascular parameters; although these were predominantly explained by age. cIMT was independently associated with classical risks and also PWV (adjusted standardized ß = 0.31, P = 0.001). However, traditional risks showed almost no independent associations with other vascular measurements. In contrast, serum phosphate and 1,25-dihydroxyvitamin D (1,25-OHD) correlated with PWV and the presence of VC, respectively. After adjustment, every 1 pg/mL increase in 1,25-OHD was related to a 3% reduction in the chance of VC (odds ratio 0.97; 95% confidence interval 0.94-1.00, P = 0.03). Medication use, HOMA-IR and C-reactive protein did not correlate with any of the vascular measures. CONCLUSIONS: This study demonstrates extensive vascular disease across multimodality imaging in moderate CKD. Atherosclerotic burden correlated with traditional risks and PWV, while higher 1,25-OHD was associated with less VC. The lack of association between renal function and imaging indices raises the possibility of a threshold, rather than graded uraemic effect on vascular health that warrants further exploration.

Acute elevation of triglycerides increases left ventricular contractility and alters ventricular-vascular interaction.

Acute elevation of circulating lipids, such as the postprandial state, contributes to increased cardiovascular risk. However, the effect of acutely elevated triglycerides on arterial and left ventricular function is not completely understood. We aimed to assess whether an acute increase in triglycerides affects ventricular-vascular interaction. Fifteen healthy men (age, 49 ± 8 yr) underwent blinded, randomized infusion of saline and intravenous fat emulsion to acutely raise plasma triglycerides. All subjects underwent both randomization trials, in random order on two separate days. Ventricular-vascular interaction measures were recorded by tonometry (central blood pressure) and echocardiography (left ventricular volumes, strain, and strain rate) at baseline and after 1 h infusion. Net ventricular-vascular interaction was defined by the effective arterial elastance (E(A))-to-left ventricular end-systolic elastance (E(LV)) ratio (E(A)/E(LV)). When compared with saline, the infusion of intravenous fat emulsion increased triglycerides and free fatty acids (ΔP < 0.001 for both) and improved left ventricular contractility (ΔE(LV), end-systolic volume and strain rate; P < 0.05 for all). However, arterial function was unchanged (ΔE(A), brachial and central blood pressure; P > 0.05 for all). Overall, E(A)/E(LV) was decreased by an infusion of intravenous fat emulsion (P = 0.004) but not saline (P > 0.05, P = 0.001 for Δ between trials). We conclude that intravenous fat emulsion and acute elevation of blood lipids (including triglycerides and free fatty acids) alter ventricular-vascular interaction by increasing left ventricular contractility without affecting arterial load. These findings may have implications for cardiovascular responses to parenteral nutrition.

Measurement of arterial distensibility and compliance to assess prognosis.

BACKGROUND AND AIM: Total arterial compliance (TAC) reflects arterial function in the entire systemic circulation while distensibility coefficient (DC) is an estimate of local arterial compliance obtained from large elastic arteries. There are few studies relating TAC or DC to outcome. We sought whether DC or TAC predicted outcome in a primary prevention cohort with a spectrum of cardiovascular risk. METHODS: Clinical data including blood pressure (BP) and diabetes mellitus (DM) were obtained and Framingham 10-year risk was calculated in 719 primary prevention patients (373 men; age 55+/-11 years). TAC was calculated from applanation tonometry using the pulse-pressure method, 2D-echocardiography and Doppler, and DC was derived from 2D measurements of the common carotid artery and pulse pressure (PP). Cox regression analysis was performed to determine correlates of outcome. RESULTS: There were 42 deaths (5.8%) and 114 cardiovascular admissions (15.8%) over 57 months. The independent correlates of mortality were Framingham 10-year risk (HR=1.69; p<0.0001) and DC (HR=0.54; p=0.02) (model chi-square 24.52; p<0.0001) but not TAC. The independent predictors of the composite outcome of either death or admission for cardiovascular causes were Framingham 10-year risk (HR=1.28; p=0.001) and TAC (HR=0.75; p=0.006) (model chi-square 21.43; p<0.0001) but not DC. CONCLUSIONS: Measurement of arterial function is independently correlated with outcome in patients with varying degrees of cardiovascular risk, and different aspects identify fatal and non-fatal events. In addition, measurement of TAC and DC adds incremental benefit to Framingham risk scores alone in patients with intermediate cardiovascular risk.

Feasibility and accuracy of different techniques of two-dimensional speckle based strain and validation with harmonic phase magnetic resonance imaging.

BACKGROUND: Different 2-dimensional speckle-based strain techniques have been developed to overcome the problem of angle dependency with Doppler-based strain. However, their relative accuracy has not been assessed. The aim of this study was to determine the feasibility and accuracy of 2 such techniques (velocity vector imaging [VVI] and automated function imaging [AFI]), using tagged harmonic phase (HARP) magnetic resonance imaging (MRI) as a reference standard. METHODS: Thirty patients with known or suspected ischemic heart disease underwent measurement of peak systolic longitudinal, radial, and circumferential Lagrangian strain with all 3 techniques using a 16-segment model. The extent of scar tissue in each segment was determined using contrast-enhanced MRI. RESULTS: The measurement of myocardial strain in all 3 directions was highly feasible with both VVI and AFI. Longitudinal strain was underestimated by both VVI (-11 +/- 8%; P < .01) and AFI (-12 +/- 6%; P < .01) in comparison with HARP MRI (-14 +/- 5%), and radial strain was underestimated by VVI (14 +/- 18% vs 23 +/- 7%; P < .01). All strain measurements with AFI showed better correlation and agreement with HARP MRI compared with VVI. Circumferential strain with AFI had the greatest accuracy (area under the receiver operating characteristic curve = 0.74, P < .001) for the prediction of scar tissue on MRI. CONCLUSIONS: Two-dimensional strain measured with AFI has significantly better accuracy than VVI. Circumferential strain with AFI has the best discriminative ability for the detection of regional myocardial dysfunction.