Paul Steendijk

Effect of Posterolateral Scar Tissue on Clinical and Echocardiographic Improvement After Cardiac Resynchronization Therapy

Background— Currently, one third of patients treated with cardiac resynchronization therapy (CRT) do not respond. Nonresponse to CRT may be explained by the presence of scar tissue in the posterolateral left ventricular (LV) segments, which may result in ineffective LV pacing and inadequate LV resynchronization. In the present study, the relationship between transmural posterolateral scar tissue and response to CRT was evaluated. Methods and Results— Forty consecutive patients with end-stage heart failure (NYHA class III/IV), LV ejection fraction ≤35%, QRS duration >120 ms, left bundle-branch block, and chronic coronary artery disease were included. The localization and transmurality of scar tissue were evaluated with contrast-enhanced MRI. Next, LV dyssynchrony was assessed at baseline and immediately after implantation with tissue Doppler imaging. Clinical parameters, LV volumes, and LV ejection fraction were assessed at baseline and at a 6-month follow-up. Fourteen patients (35%) had a transmural (>50% of LV wall thickness) posterolateral scar. In contrast to patients without posterolateral scar tissue, these patients showed a low response rate (14% versus 81%; P<0.05) and did not show improvement in clinical or echocardiographic parameters. In addition, LV dyssynchrony remained unchanged after CRT implantation (84±46 versus 78±41 ms; P=NS). Patients without posterolateral scar tissue and severe baseline dyssynchrony (≥65 ms) showed an excellent response rate of 95% compared with patients with a posterolateral scar and/or absent LV dyssynchrony (11%). Conclusions— CRT does not reduce LV dyssynchrony in patients with transmural scar tissue in the posterolateral LV segments, resulting in clinical and echocardiographic nonresponse to CRT.

Utility of Doppler Echocardiography and Tissue Doppler Imaging in the Estimation of Diastolic Function in Heart Failure With Normal Ejection Fraction A Comparative Doppler-Conductance Catheterization Study

Background— Various conventional and tissue Doppler echocardiographic indexes were compared with pressure–volume loop analysis to assess their accuracy in detecting left ventricular (LV) diastolic dysfunction in patients with heart failure with normal ejection fraction (HFNEF). Methods and Results— Diastolic dysfunction was confirmed by pressure–volume loop analysis obtained by conductance catheter in 43 patients (19 men) with HFNEF. Their Doppler indexes were compared with those of 12 control patients without heart failure symptoms and with normal ejection fraction. Invasively measured indexes for diastolic relaxation (&tgr;, dP/dtmin), LV end-diastolic pressure, and LV end-diastolic pressure–volume relationship (stiffness, b [dP/dV], and stiffness constant, &bgr;) were correlated with several conventional mitral flow and tissue Doppler imaging indexes. Conventional Doppler indexes correlated moderately with the degree of LV relaxation index, &tgr; (E/A: r=−0.36, P=0.013; isovolumic relaxation time: r=0.31, P=0.040) and b (deceleration time: r=0.39, P=0.012) but not with &bgr;, in contrast to the tissue Doppler imaging indexes E’/A’lateral (r=−0.37, P=0.008) and E/E’lateral (r=0.53, P<0.001). Diastolic dysfunction was detected in 70% of the HFNEF patients by mitral flow Doppler but in 81% and 86% by E’/A’lateral, and E/E’lateral, respectively. Conclusions— Of all echocardiographic parameters investigated, the LV filling index E/E’lateral was identified as the best index to detect diastolic dysfunction in HFNEF in which the diagnosis of diastolic dysfunction was confirmed by conductance catheter analysis. We recommend its use as an essential tool for noninvasive diagnostics of diastolic function in patients with HFNEF.

Relationship between QRS duration and left ventricular dyssynchrony in patients with end-stage heart failure.

Introduction: Patients with end‐stage heart failure and a wide QRS complex are considered candidates for cardiac resynchronization therapy (CRT). However, 20% to 30% of patients do not respond to CRT. Lack of left ventricular dyssynchrony may explain the nonresponse. Accordingly, we evaluated the presence of left ventricular dyssynchrony using tissue Doppler imaging (TDI) in 90 consecutive patients with heart failure.

Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury

OBJECTIVES This study sought to examine whether exenatide is capable of reducing myocardial infarct size. BACKGROUND Exenatide is a glucagon-like peptide (GLP)-1 analogue with insulinotropic and insulinomimetic properties. Because insulin and GLP-1 have been described as reducing apoptosis, exenatide might confer cardioprotection after acute myocardial infarction (MI). METHODS Pigs were randomized to exenatide or phosphate-buffered saline (PBS) treatment after 75 min of coronary artery ligation and subsequent reperfusion. Infarct size was assessed with Evans Blue (Sigma-Aldrich, St. Louis, Missouri) and triphenyltetrazolium chloride. Cardiac function was measured with epicardial ultrasound and conductance catheter-based pressure-volume loops. Western blotting, histology, and activity assays were performed to determine markers of apoptosis/survival and oxidative stress. RESULTS Exenatide reduced myocardial infarct size (32.7 +/- 6.4% vs. 53.6 +/- 3.9%; p = 0.031) and prevented deterioration of systolic and diastolic cardiac function (systolic wall thickening: 47.3 +/- 6.3% vs. 8.1 +/- 1.9%, p < 0.001; myocardial stiffness: 0.12 +/- 0.06 mm Hg/ml vs. 0.22 +/- 0.07 mm Hg/ml; p = 0.004). After exenatide treatment, myocardial phosphorylated Akt and Bcl-2 expression levels were higher compared with those after PBS treatment, and active caspase 3 expression was lower. In addition, fewer cells were terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling-positive. In addition, nuclear oxidative stress as assessed with an 8-hydroxydeoxyguanosine staining was reduced in the exenatide treatment arm, and superoxide dismutase activity and catalase activity were increased. Serum insulin levels increased after exenatide treatment, without affecting glucose levels. CONCLUSIONS These data identify exenatide as a potentially effective compound to reduce infarct size in adjunction to reperfusion therapy in patients with acute MI.

Role of Left Ventricular Stiffness in Heart Failure With Normal Ejection Fraction

Background— Increased left ventricular stiffness is a distinct finding in patients who have heart failure with normal ejection fraction (HFNEF). To elucidate how diastolic dysfunction contributes to heart failure symptomatology during exercise, we conducted a study using an invasive pressure-volume loop approach and measured cardiac function at rest and during atrial pacing and handgrip exercise. Methods and Results— Patients with HFNEF (n=70) and patients without heart failure symptoms (n=20) were enrolled. Pressure-volume loops were measured with a conductance catheter during basal conditions, handgrip exercise, and atrial pacing with 120 bpm to analyze diastolic and systolic left ventricular function. During transient preload reduction, the diastolic stiffness constant was measured directly. Diastolic function with increased stiffness was significantly impaired in patients with HFNEF during basal conditions. This was associated with increased end-diastolic pressures during handgrip exercise and with decreased stroke volume and a leftward shift of pressure-volume loops during atrial pacing. Conclusions— Increased left ventricular stiffness contributed to increased end-diastolic pressure during handgrip exercise and decreased stroke volume during atrial pacing in patients with HFNEF. These data suggest that left ventricular stiffness modulates cardiac function in HFNEF patients and suggests that diastolic dysfunction with increased stiffness is a target for treating HFNEF.

Magnetic Resonance Imaging Analysis of Right Ventricular Pressure-Volume Loops In Vivo Validation and Clinical Application in Patients With Pulmonary Hypertension

Background—The aims of this study were to validate MRI-derived right ventricular (RV) pressure-volume loops for assessment of RV myocardial contractility and then to apply this technique in patients with chronic RV pressure overload for assessment of myocardial contractility, ventricular pump function, and VA coupling. Methods and Results—Flow-directed catheters were guided under MR fluoroscopy (1.5 T) into the RV for invasive pressure measurements. Simultaneously, ventricular volumes and myocardial mass were assessed from cine MRI. From sampled data, RV pressure-volume loops were constructed, and maximal ventricular elastance indexed to myocardial mass (Emax_i) was derived by use of a single-beat estimation method. This MRI method was first validated in vivo (6 swine), with conductance techniques used as reference. Bland-Altman test showed good agreement between methods (Emax_i=5.1±0.5 versus 5.8±0.7 mm Hg · mL−1 · 100 g−1, respectively; P=0.08). Subsequently, the MRI method was applied in 12 subjects: 6 control subjects and 6 patients with chronic RV pressure overload from pulmonary hypertension. In these patients, indexes of RV pump function (cardiac index), Emax_i, and VA coupling (Emax/Ea) were assessed. In patients with pulmonary hypertension, RV pump function was decreased (cardiac index, 2.2±0.5 versus 2.9±0.4 L · min−1 · m−2; P<0.01), myocardial contractility was enhanced (Emax_I, 9.2±1.1 versus 5.0±0.9 mm Hg · mL−1 · 100 g−1; P<0.01), and VA coupling was inefficient (Emax/Ea, 1.1±0.3 versus 1.9±0.4; P<0.01) compared with control subjects. Conclusions—RV myocardial contractility can be determined from MRI-derived pressure-volume loops. Chronic RV pressure overload was associated with reduced RV pump function despite enhanced RV myocardial contractility. The proposed MRI approach is a promising tool to assess RV contractility in the clinical setting.

Cardiac Inflammation Contributes to Changes in the Extracellular Matrix in Patients With Heart Failure and Normal Ejection Fraction

Background—The pathophysiology of heart failure with normal ejection fraction (HFNEF) is still under discussion. Here we report the influence of cardiac inflammation on extracellular matrix (ECM) remodeling in patients with HFNEF. Methods and Results—We investigated left ventricular systolic and diastolic function in 20 patients with HFNEF and 8 control patients by conductance catheter methods and echocardiography. Endomyocardial biopsy samples were also obtained, and ECM proteins as well as cardiac inflammatory cells were investigated. Primary human cardiac fibroblasts were outgrown from the endomyocardial biopsy samples to investigate the gene expression of ECM proteins after stimulation with transforming growth factor-&bgr;. Diastolic dysfunction was present in the HFNEF patients compared with the control patients. In endomyocardial biopsy samples from HFNEF patients, we found an accumulation of cardiac collagen, which was accompanied by a decrease in the major collagenase system (matrix metalloproteinase-1) in the heart. Moreover, a subset of inflammatory cells, which expressed the profibrotic growth factor transforming growth factor-&bgr;, could be documented in the HFNEF patients. Stimulation of primary human cardiac fibroblasts from HFNEF patients with transforming growth factor-&bgr; resulted in transdifferentiation of fibroblasts to myofibroblasts, which produced more collagen and decreased the amount of matrix metalloproteinase-1, the major collagenase in the human heart. A positive correlation between cardiac collagen, as well as the amount of inflammatory cells, and diastolic dysfunction was evident and suggests a direct influence of inflammation on fibrosis triggering diastolic dysfunction. Conclusions—Cardiac inflammation contributes to diastolic dysfunction in HFNEF by triggering the accumulation of ECM.

Optimizing Hemodynamics in Heart Failure Patients by Systematic Screening of Left Ventricular Pacing Sites : The Lateral Left Ventricular Wall and the Coronary Sinus Are Rarely the Best Sites

OBJECTIVES We sought to evaluate the impact of the left ventricular (LV) pacing site on hemodynamic response to cardiac resynchronization therapy (CRT). BACKGROUND CRT reduces morbidity and mortality in heart failure patients. However, 20% to 40% of eligible patients may not fully benefit from CRT device implantation. We hypothesized that selecting the optimal LV pacing site could be critical in this issue. METHODS Thirty-five patients with nonischemic dilated cardiomyopathy referred for CRT device implantation were studied. Intraventricular dyssynchrony and latest activated LV wall were defined by tissue Doppler imaging analysis before the study. Eleven predetermined LV pacing sites were systematically assessed in random order: basal and mid-cavity (septal, anterior, lateral, inferior), apex, coronary sinus (CS), and the endocardial site facing the CS pacing site. For each patient, +dP/dT(max), -dP/dT(min), pulse pressure, and end-systolic pressure during baseline (AAI) and DDD LV pacing were compared. Two atrioventricular delays were tested. RESULTS Major interindividual and intraindividual variations of hemodynamic response depending on the LV pacing site were observed. Compared with baseline, LV DDD pacing at the best LV position significantly improved +dP/dT(max) (+31 +/- 26%, p < 0.001) and was superior to pacing the CS (+15 +/- 23%, p < 0.001), the lateral LV wall (+18 +/- 22%, p < 0.001), or the latest activated LV wall (+11 +/- 17%, p < 0.001). CONCLUSIONS The pacing site is a primary determinant of the hemodynamic response to LV pacing in patients with nonischemic dilated cardiomyopathy. Pacing at the best LV site is associated acutely with fewer nonresponders and twice the improvement in +dP/dT(max) observed with CS pacing.

Usefulness of myocardial tissue Doppler echocardiography to evaluate left ventricular dyssynchrony before and after biventricular pacing in patients with idiopathic dilated cardiomyopathy

Tissue Doppler imaging allows assessment of left ventricular dyssynchrony and resynchronization after biventricular pacing.

Assessing right ventricular function: the role of echocardiography and complementary technologies

The physiological importance of the right ventricle (RV) has been underestimated; the RV was considered mainly as a conduit whereas its contractile performance was thought to be haemodynamically unimportant.1 However, its essential contribution to normal cardiac pump function is well established with the primary RV functions being: RV function may be impaired either by primary right sided heart disease, or secondary to left sided cardiomyopathy or valvar heart disease.2 In addition, it should be considered that RV dysfunction may affect left ventricular (LV) function, not only by limiting LV preload, but also by adverse systolic and diastolic interaction via the intraventricular septum and the pericardium (ventricular interdependence). Moreover, RV function has been shown to be a major determinant of clinical outcome3–9 and consequently should be considered during clinical management and treatment.10 Thus, the need for diagnosis of RV dysfunction is evident. In practice, clinicians largely rely on non-invasive imaging methods for assessment of RV function. Two dimensional echocardiography is the mainstay for analysis of RV function, but recently alternative techniques have been proposed, including tissue Doppler imaging (TDI) techniques,11 three dimensional echocardiography,12 magnetic resonance imaging (MRI), and even invasive assessment of pressure–volume loops.13–17 An overview of these imaging modalities for assessment of RV function is provided in the current manuscript. Due to its widespread availability, echocardiography is used as the first line imaging modality for assessment of RV size and RV function. The quantitative assessment of RV size and function is often difficult, because of the complex anatomy. Nevertheless, when used …