Tony Stanton

Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring.

Background—Although global left ventricular systolic function is an important determinant of mortality, standard measures such as ejection fraction (EF) and wall motion score index (WMSI) have important technical limitations. The aim of this study was to compare global longitudinal speckle strain (GLS), an automated technique for measurement of long-axis function, with EF and WMSI for the prediction of mortality. Methods and Results—Of 546 consecutive individuals undergoing echocardiography for assessment of resting left ventricular function, 91 died over a period of 5.2±1.5 years. In addition to Simpson biplane EF, WMSI was determined by 2 experienced readers and GLS was calculated from 3 standard apical views using 2D speckle tracking. The incremental value of EF, WMSI, and GLS to significant clinical variables was assessed in nested Cox models. Clinical factors associated with outcome (model &khgr;2=20.2) were age (hazard ratio [HR], 1.46; P<0.01), diabetes (HR, 1.88; P=0.01), and hypertension (HR, 1.59; P<0.05). Although addition of EF (HR, 1.23; P=0.03) or WMSI (HR, 1.28; P<0.01) added to the predictive power of clinical variables, the addition of GLS (HR, 1.45; P<0.001) caused the greatest increment in model power (&khgr;2=34.9, P<0.001). GLS also provided incremental value in subgroups with EF >35% and those with and without wall motion abnormalities. A GLS ≥−12% was found to be equivalent to an EF ≤35% for the prediction of prognosis. Intraobserver and interobserver variations for EF and GLS were similar. Conclusions—GLS is a superior predictor of outcome to either EF or WMSI and may become the optimal method for assessment of global left ventricular systolic function.Background— Although global left ventricular systolic function is an important determinant of mortality, standard measures such as ejection fraction (EF) and wall motion score index (WMSI) have important technical limitations. The aim of this study was to compare global longitudinal speckle strain (GLS), an automated technique for measurement of long-axis function, with EF and WMSI for the prediction of mortality. Methods and Results— Of 546 consecutive individuals undergoing echocardiography for assessment of resting left ventricular function, 91 died over a period of 5.2±1.5 years. In addition to Simpson biplane EF, WMSI was determined by 2 experienced readers and GLS was calculated from 3 standard apical views using 2D speckle tracking. The incremental value of EF, WMSI, and GLS to significant clinical variables was assessed in nested Cox models. Clinical factors associated with outcome (model χ2=20.2) were age (hazard ratio [HR], 1.46; P 35% and those with and without wall motion abnormalities. A GLS ≥−12% was found to be equivalent to an EF ≤35% for the prediction of prognosis. Intraobserver and interobserver variations for EF and GLS were similar. Conclusions— GLS is a superior predictor of outcome to either EF or WMSI and may become the optimal method for assessment of global left ventricular systolic function. Received March 9, 2009; accepted July 17, 2009. # CLINICAL PERSPECTIVE {#article-title-2}

Protein-bound uremic toxins, inflammation and oxidative stress: A cross-sectional study in stage 3-4 chronic kidney disease

BACKGROUND AND AIMS Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are nephro- and cardiovascular toxins, produced solely by the gut microbiota, which have pro-inflammatory and pro-oxidative properties in vitro. We undertook this study to investigate the associations between IS and PCS and both inflammation and oxidative stress in the chronic kidney disease (CKD) population. METHODS In this cross-sectional observational cohort study, participants with stage 3-4 CKD who enrolled in a randomized controlled trial of cardiovascular risk modification underwent baseline measurements of serum total and free IS and PCS (measured by ultraperformance liquid chromotography), inflammatory markers (interferon gamma [IFN-γ], interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-α]), antioxidant and oxidative stress markers (plasma glutathione peroxidase [GPx] activity, total antioxidant capacity [TAC] and F2-isoprostanes) and pulse wave velocity (PWV), a marker of arterial stiffness. RESULTS There were 149 CKD patients (59% male; age 60 ± 10 years; 44% diabetic) with a mean eGFR of 40 ± 9 mL/min/1.73 m(2) (range 25-59). Serum free and total IS were independently associated with serum IL-6, TNF-α and IFN-γ, whereas serum free and total PCS were independently associated with serum IL-6 and PWV. Free IS and PCS were additionally independently associated with serum GPx but not with TAC or F2-isoprostanes. CONCLUSIONS IS and PCS were associated with elevated levels of selected inflammatory markers and an antioxidant in CKD patients. PCS was also associated with increased arterial stiffness. Inflammation and oxidative stress may contribute to the nephro- and cardiovascular toxicities of IS and PCS. Intervention studies targeting production of IS and PCS by dietary manipulation and the subsequent effect on cardiovascular-related outcomes are warranted in the CKD population.

How should we optimize cardiac resynchronization therapy

Optimization of cardiac resynchronization therapy is increasingly performed. Numerous methods have been proposed, many being echocardiographic. Both the technique and the timing of optimization are contentious. Whether acute haemodynamic benefits translate into long-term improvements in remodelling, symptoms, or prognosis is unknown. Recent guidelines from the American Society of Echocardiography advocate routine optimization. Here, we objectively review the principles, methods, timing, and evidence supporting optimization. Despite limited validation, optimization was included in landmark clinical trials and is inherent in evidence-based practice. Randomized controlled trials comparing methods are needed, with long-term clinical endpoints. For now, optimization should be performed using the iterative method, according to the CARE-HF protocol.

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 (χ2=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).

Assessment of subendocardial structure and function.

The combination of high energy expenditure and the borderline adequacy of perfusion make the subendocardium uniquely vulnerable to injury. Selective subendocardial involvement is usually a marker of subclinical disease. Technical advances in new noninvasive imaging modalities, especially in spatial resolution, now permit qualitative and quantitative assessment of subendocardial structure, function, and perfusion. Many newer techniques have the potential to provide superior prognostic information to current standard assessment methods. This review describes the contemporary capabilities of multiple imaging modalities for assessment of the subendocardium, and seeks to guide the clinician regarding the information and technical deficiencies of each modality.

Usefulness of at rest and exercise hemodynamics to detect subclinical myocardial disease in type 2 diabetes mellitus

Patients with type 2 diabetes mellitus (T2DM) might have subclinical myocardial dysfunction identified at rest or unmasked during exercise. We examined the correlates of the myocardial exercise response in patients with T2DM. Myocardial dysfunction was sought during at rest and exercise echocardiography in 167 healthy patients with T2DM (97 men, 55 ± 10 years). Myocardial ischemia was excluded using stress echocardiography. Standard echocardiography and color tissue Doppler imaging measures (early diastolic tissue velocity [Em], strain, and strain rate) were acquired at baseline and peak stress. The calibrated integrated backscatter was calculated from the at rest parasternal long-axis view. The longitudinal diastolic functional reserve index after exercise was defined as ΔEm [1 - (1/Em(base))]. The clinical, anthropometric, and metabolic data were collected at rest and stress. Subclinical myocardial dysfunction at baseline (n = 24) was independently associated with weight (odds ratio [OR] 1.02, p = 0.04) and hemoglobin A1c (OR 1.36, p = 0.03). This group displayed an impaired exercise response that was independently associated with a reduced exercise capacity (OR 0.84, p = 0.034) and longitudinal diastolic functional reserve index (OR 0.69, p = 0.001). Inducible myocardial dysfunction (stress Em <-9.9 cm/s) was identified after exercise in 70 of the remaining 143 subjects. This finding was associated with calibrated integrated backscatter (OR 1.08, p = 0.04) and lower peak heart rate (OR 0.97, p = 0.002) but not metabolic control. The intensity of the metabolic derangement in patients with T2DM was associated with subclinical at rest myocardial dysfunction, but not with the myocardial exercise response. In conclusion, the association of an abnormal stress response with nonmetabolic factors, including backscatter and blunted peak heart rate, suggests potential roles for myocardial fibrosis and cardiac autonomic neuropathy in patients with nonischemic diabetic heart disease.

Fixed dose combination therapy in the treatment of hypertension

Raised blood pressure is a common and quantitatively important cardiovascular risk factor. Over 50% of over 65’s in industrialised countries may be considered to have hypertension and 50% of people in this age group go on to die a cardiovascular death such as myocardial infarct or stroke. Studies have clearly demonstrated the benefit and safety of an aggressive strategy of blood pressure lowering with targets of below 140 mm Hg systolic and 90 mm Hg diastolic. Hypertension-induced stroke appears to be largely preventable and a significant reduction is seen in hypertension-attributable ischaemic heart disease when the above targets are achieved. Reaching and maintaining these targets in the majority of patients however presents a clinical challenge. Currently several drug classes can be utilised in the treatment of hypertension: thiazide diuretics, beta ( )-blockers, calcium channel blockers (CCB’s), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II (AII) receptor blockers, alpha ( ) blockers and centrally acting agents. Both the British Hypertension Society 1999 guidelines and the American 6th Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Blood Pressure (JNC VI) of 1997 recommend that, in the absence of contra-indications or compelling indications for other agents, thiazide diuretics and blockers are the drugs of choice. These drugs have proved to be both safe and efficacious in numerous randomised control trials. Practice has been to begin treatment with one of these agents as monotherapy at a low dose. If this does not control blood pressure adequately then the physician is faced with three options.

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.

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 Simpsons 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.

Hypertension and myocardial ischemia.

Detailed studies over the past 30 years have built up an impressive evidence base for the presence of myocardial ischemia in patients who have hypertension. This relationship ranges from the obvious association with obstructive coronary artery disease to mechanisms related to hemodynamic, microcirculatory, and neuroendocrine abnormalities. All of these factors serve to destabilize the critical balance between myocardial oxygen supply and demand. We have at our disposal a range of sophisticated investigations that allow us to demonstrate the presence and extent of the ischemia and therefore to target specific therapies to reduce the risk to these patients. Achieving target BP and managing all reversible components of the patients cardiovascular risk status reduce to a minimum the clinical sequelae of myocardial ischemia in this vulnerable population..