Peter Hanrath

Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.

BACKGROUND Beta blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. METHODS In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. FINDINGS The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. INTERPRETATION Our results suggest that carvedilol extends survival compared with metoprolol.

Analysis of interinstitutional observer agreement in interpretation of dobutamine stress echocardiograms

OBJECTIVES This study sought to determine the degree of interinstitutional agreement in the interpretation of dobutamine stress echocardiograms. BACKGROUND Dobutamine stress echocardiography involves subjective interpretation. Consistent methods for acquisition and interpretation are of critical importance for obtaining high interobserver agreement and for facilitating communication of test results. METHODS Five experienced centers were each asked to submit 30 dobutamine stress echocardiograms (dobutamine up to 40 micrograms/kg body weight per min and atropine up to 1 mg) obtained in patients undergoing coronary angiography. Thus, a total of 150 dobutamine stress echocardiograms were interpreted by each center without knowledge of any other patient data. Left ventricular wall motion was assessed using a 16-segment model but was otherwise not standardized. No patient was excluded because of poor image quality or inadequate stress level. Echocardiographic image quality was assessed using a five-point scale. RESULTS Angiographically significant coronary artery disease (> or = 50% diameter stenosis) was present in 95 patients (63%). By a majority decision (three or more centers), the sensitivity, specificity and accuracy of dobutamine echocardiography were 76%, 87% and 80%, respectively. Abnormal or normal results of stress echocardiography were agreed on by four or all five of the centers in 73% of patients (mean kappa value 0.37, fair agreement only). Agreement on the left anterior descending artery territory (78%) was similar to that for the combined right coronary artery/left circumflex artery territory (74%), and for specific segments the agreement ranged from 84% to 97% and was highest for the basal anterior segment and lowest for the basal inferior segment. Agreement was higher in patients with no (82%) or three-vessel coronary artery disease (100%) and lower in patients with one- or two-vessel disease (61% and 68%, respectively). Agreement on positivity or negativity of stress test results was 100% for patients with the highest image quality but only 43% for those with the lowest image quality (p = 0.003). CONCLUSIONS The current heterogeneity in data acquisition and assessment criteria among different centers results in low interinstitutional agreement in interpretation of stress echocardiograms. Agreement is higher in patients with no or advanced coronary artery disease and substantially lower in those with limited echocardiographic image quality. To increase interinstitutional agreement, better standardization of image acquisition and reading criteria of stress echocardiography is recommended.

Left ventricular relaxation and filling pattern in different forms of left ventricular hypertrophy: An echocardiographic study☆

Abstract To study left ventricular relaxation and filling in different forms of left ventricular hypertrophy, echocardiograms of the left ventricle in 24 patients with hypertrophic obstructive cardiomyopathy and in 24 patients with chronic left ventricular pressure overload (due to aortic stenosis in 6 and to severe arterial hypertension in 18) were analyzed by computer and compared with those of 28 normal subjects. The relaxation time index (minimal left ventricular dimension to mitral valve opening) was 13 ± 15 ms in normal subjects. This index was prolonged in patients with cardiomyopathy (93 ± 37 ms) and overload (66 ± 31 ms). During the interval from minimal left ventricular dimension to mitral valve opening both groups with left ventricular hypertrophy showed a marked increase in left ventricular dimension of 4.0 ± 2.2 mm and 3.0 ±1.8 mm, respectively, which was significantly greater (p The rapid filling phase and the increase in dimension during this period were significantly reduced in hypertrophic obstructive cardiomyopathy and chronic pressure overload. In contrast to findings in the patients with cardiomyopathy, in those with pressure overload the reduced increase in left ventricular dimension during the rapid diastolic filling period was compensated for by a greater dimensional increase due to atrial contraction, resulting in a normal end-diastolic dimension. These data indicate that significant prolongation of isovolumic relaxation is seen in different forms of left ventricular hypertrophy and is often associated with an abnormal diastolic filling pattern.

Deposition of Platelet RANTES Triggering Monocyte Recruitment Requires P-Selectin and Is Involved in Neointima Formation After Arterial Injury

Background—Chemokines expressed on atherosclerotic endothelium or deposited by activated platelets have been implicated in monocyte recruitment during atherogenesis and restenosis. Although the involvement of P-selectin in these processes is evident from studies in knockout mice, it has not been elucidated whether delivery of platelet chemokines requires P-selectin, thus serving as a P-selectin-dependent effector function. Methods and Results—Using immunofluorescence and laminar flow assays, we found that the deposition of the platelet-derived chemokine RANTES and monocyte arrest subsequently triggered by RANTES immobilized on inflamed endothelium are more efficient after preperfusion than after static preincubation of platelets and appear to depend on interactions of platelet but not endothelial P-selectin. This was revealed by the effects of P-selectin antibodies and comparison of P-selectin-deficient and wild-type platelets. Immunohistochemistry detected a substantial luminal expression of RANTES on neointimal lesions in wire-injured carotid arteries of apolipoprotein E (apoE)-deficient mice but not of mice with a combined deficiency in apoE and P-selectin (or platelet P-selectin). As assessed by histomorphometry, treatment of apoE-deficient mice with the RANTES receptor antagonist Met-RANTES markedly reduced neointimal plaque area and macrophage infiltration. Conclusions—Our data suggest that RANTES deposition and subsequent monocyte arrest are promoted by platelet P-selectin and involved in wire-induced intimal hyperplasia, and that blocking RANTES receptors attenuates neointima formation and macrophage infiltration. This mechanism represents an important component explaining the protection against neointimal growth in P-selectin-deficient mice and may represent a novel approach to the treatment of restenosis or atherosclerosis by the administration of chemokine receptor antagonists.

Cardiac resynchronization therapy can reverse abnormal myocardial strain distribution in patients with heart failure and left bundle branch block.

OBJECTIVES We studied the effects of cardiac resynchronization therapy (CRT) on regional myocardial strain distribution, as determined by echocardiographic strain rate (SR) imaging. BACKGROUND Dilated hearts with left bundle branch block (LBBB) have an abnormal redistribution of myocardial fiber strain. The effects of CRT on such abnormal strain patterns are unknown. METHODS We studied 18 patients (12 males and 6 females; mean age 65 +/- 11 years [range 33 to 76 years]) with symptomatic systolic heart failure and LBBB. Doppler myocardial imaging studies were performed to acquire regional longitudinal systolic velocity (cm/s), systolic SR (s(-1)), and systolic strain (%) data from the basal and mid-segments of the septum and lateral wall before and after CRT. By convention, negative SR and strain values indicate longitudinal shortening. RESULTS Before CRT, mid-septal peak SR and peak strain were lower than in the mid-lateral wall (peak SR: -0.79 +/- 0.5 [septum] vs. -1.35 +/- 0.8 [lateral wall], p < 0.05; peak strain: -7 +/- 5 [septum] vs. -11 +/- 5 [lateral wall], p < 0.05). This relationship was reversed during CRT (peak SR: -1.35 +/- 0.8 [septum] vs. -0.93 +/- 0.6 [lateral wall], p < 0.05; peak strain: -11 +/- 6 [septum] vs. -7 +/- 6 [lateral wall], p < 0.05). Cardiac resynchronization therapy reversed the septal-lateral difference in mid-segmental peak strain from -46 +/- 94 ms (LBBB) to 17 +/- 92 ms (CRT; p < 0.05). CONCLUSIONS Left bundle branch block can lead to a significant redistribution of abnormal myocardial fiber strains. These abnormal changes in the extent and timing of septal-lateral strain relationships can be reversed by CRT. The noninvasive identification of specific abnormal but reversible strain patterns should help to improve patient selection for CRT.

Statin Treatment After Onset of Sepsis in a Murine Model Improves Survival

Background—HMG-CoA-reductase inhibitors have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering. We have recently demonstrated that pretreatment with simvastatin profoundly improves survival in a cecal ligation and perforation (CLP) model of sepsis. Here, we studied whether treatment with simvastatin after onset of sepsis-induced hemodynamic alterations is beneficial and whether prolonged survival can also be achieved with other statins. Methods and Results—Mice were rendered septic by CLP. At 6 hours after sepsis induction, when profound hemodynamic alterations were manifest, treatment with atorvastatin, fluvastatin, pravastatin, simvastatin, or placebo was initiated. Except for fluvastatin (27±2.3 hours), survival time was extended from 23±1.2 hours for placebo-treated mice to 37±3.6 hours for simvastatin-treated, to 40±4.2 hours for atorvastatin-treated, and to 39±3.9 hours for pravastatin-treated mice. This profound improvement is based on the preservation of cardiac function and hemodynamic status in statin-treated animals, both of which are severely impaired in untreated CLP mice. As underlying mechanisms, improved susceptibility to endothelial nitric oxide synthase stimulation and reduced endothelial adhesion of leukocytes could be demonstrated after statin treatment. Conclusions—Well established in the treatment of lipid disorders and coronary artery disease, statins harbor the additional and novel potential of effective sepsis treatment. This benefit extends to several but not all statins tested.

HMG-CoA Reductase Inhibitor Simvastatin Profoundly Improves Survival in a Murine Model of Sepsis

Background—HMG-CoA reductase inhibitors, such as simvastatin, have been shown to exhibit pronounced immunomodulatory effects independent of lipid lowering but to date have not been used to treat severe inflammatory disease such as sepsis. We thus approached the question of whether treatment with simvastatin might improve cardiovascular function and survival in sepsis. Methods and Results—Mice treated with simvastatin and rendered septic by cecal ligation and perforation (CLP) show a mean survival time close to 4 times the value found in untreated mice. This dramatic improvement is based on a complete preservation of cardiac function and hemodynamic status, which are severely impaired in untreated CLP mice [eg, 20 hours after CLP, cardiac output declined from 1.24±0.09 to 0.87±0.11 mL · min−1 · g−1 in untreated mice (P <0.005; n=12), while remaining unaltered (1.21±0.08 mL · min−1 · g−1 at baseline and 1.15±0.1 mL · min−1 · g−1 20 hours after CLP, P =NS, n=12) in CLP mice treated with simvastatin]. Untreated CLP mice remained refractory to β-stimulation, whereas the responsiveness to dobutamine was restored by treatment with simvastatin. Susceptibility of coronary flow to endothelial nitric oxide synthase (eNOS) stimulation by bradykinin was close to 3 times as pronounced in untreated CLP mice as in untreated sham-operated mice, indicating a high level of eNOS activation secondary to sepsis. In addition, treatment with simvastatin reversed inflammatory alterations in CLP mice, namely, increased monocyte adhesion to endothelium. Conclusions—Simvastatin, which is well established in the treatment of lipid disorders and coronary artery disease, might have the additional potential of being an effective agent in sepsis treatment.

Assessment of Myocardial Reperfusion by Intravenous Myocardial Contrast Echocardiography and Coronary Flow Reserve After Primary Percutaneous Transluminal Coronary Angiography in Patients With Acute Myocardial Infarction

Background—This study investigated whether the extent of perfusion defect determined by intravenous myocardial contrast echocardiography (MCE) in patients with acute myocardial infarction (AMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) relates to coronary flow reserve (CRF) for assessment of myocardial reperfusion and is predictive for left ventricular recovery. Methods and Results—Twenty-five patients with first AMI underwent intravenous MCE with NC100100 with intermittent harmonic imaging before PTCA and after 24 hours. MCE before PTCA defined the risk region and MCE at 24 hours the “no-reflow” region. The no-reflow region divided by the risk region determined the ratio to the risk region. CFR was assessed immediately after PTCA and 24 hours later. Left ventricular wall motion score indexes were calculated before PTCA and after 4 weeks. CFR at 24 hours defined a recovery (CFR ≥1.6; n=17) and a nonrecovery group (CFR <1.6; n=8). Baseline CFR did not differ between groups. M...

Strain rate measurement by Doppler echocardiography allows improved assessment of myocardial viability in patients with depressed left ventricular function

OBJECTIVES This study sought to evaluate whether objective assessment of the myocardial functional reserve, using strain rate imaging (SRI), allows accurate detection of viable myocardium. BACKGROUND Strain rate imaging is a new echocardiographic modality that allows quantitative assessment of segmental myocardial contractility. METHODS In 37 patients (age 58 +/- 9 years) with ischemic left ventricular dysfunction, myocardial viability was assessed using low-dose (10 microg/kg body weight per min) two-dimensional dobutamine stress echocardiography (DSE), tissue Doppler imaging, SRI and (18)F-fluorodeoxyglucose ((18)FDG) positron emission tomography (PET). The peak systolic tissue Doppler velocity and peak systolic myocardial strain rate were determined at baseline and during low-dose dobutamine stress from the apical views. RESULTS A total of 192 segments with dyssynergy at rest were classified by (18)FDG PET as viable in 94 and nonviable in 98. An increase of peak systolic strain rate from rest to dobutamine stimulation by more than -0.23 1/s allowed accurate discrimination of viable from nonviable myocardium, as determined by (18)FDG PET with a sensitivity of 83% and a specificity of 84%. Receiver operating characteristic (ROC) curve analysis showed an area under the curve for prediction of nonviable myocardium, as determined by (18)FDG PET using SRI, of 0.89 (95% confidence interval [CI] 0.88 to 0.90), whereas the area under the ROC curve using tissue Doppler imaging was 0.63 (95% CI 0.61 to 0.65). CONCLUSIONS The increase in the peak systolic strain rate during low-dose dobutamine stimulation allows accurate discrimination between different myocardial viability states. Strain rate imaging is superior to two-dimensional DSE and tissue Doppler imaging for the assessment of myocardial viability.

Analysis of myocardial deformation based on pixel tracking in two dimensional echocardiographic images enables quantitative assessment of regional left ventricular function

Objective: To evaluate whether myocardial strain and strain rate calculated from two dimensional echocardiography by automatic frame-by-frame tracking of natural acoustic markers enables objective description of regional left ventricular (LV) function. Methods: In 64 patients parasternal two dimensional echocardiographic views at the apical, mid-ventricular and basal levels were obtained. An automatic frame-by-frame tracking system of natural acoustic echocardiographic markers was used to calculate radial strain, circumferential strain, radial strain rate and circumferential strain rate for each LV segment in a 16 segment model. Cardiac magnetic resonance imaging (cMRI) was performed to define segmental LV function as normokinetic, hypokinetic or akinetic. Results: Image quality was sufficient for adequate strain and strain-rate analysis from two dimensional echocardiographic images obtained from parasternal views in 88% of segments. Obtained radial strain data were highly reproducible and analysis was affected by only small intraobserver (mean 4.4 (SD 1.6)%) and interobserver variabilities (7.3 (2.5)%). Each of the analysed strain and strain-rate parameters was significantly different between segments defined as normokinetic, hypokinetic or akinetic by cMRI (radial strain 36.8 (10.5)%, 24.1 (7.5)% and 13.4 (4.8)%, respectively, p < 0.001). Peak systolic radial strain enabled detection of hypokinesis or akinesis with a sensitivity of 83.5% and a specificity of 83.5% (cut off value 29.1%, receiver operating characteristic (ROC) curve area 0.905, 95% CI 0.883 to 0.923). Peak systolic radial strain analysis also enabled detection of akinesis versus hypokinesis with a sensitivity of 82.7% and a specificity of 94.5% (cut off value 21.0%, ROC curve area 0.946). Peak systolic radial strain-rate analysis was less accurate than peak systolic radial strain analysis to detect cMRI-defined segmental function abnormalities. The accuracy of peak systolic circumferential strain and strain rate was similar to that of corresponding radial parameters. Conclusions: Frame-by-frame tracking of acoustic markers in two dimensional echocardiographic images enables accurate analysis of regional systolic LV function.