Alexander Hansen

Prognostic value of Doppler echocardiographic mitral inflow patterns: implications for risk stratification in patients with chronic congestive heart failure

OBJECTIVES This prospective study tested whether transmitral flow patterns add incremental value to peak oxygen consumption (VO2) in determining the prognosis of patients with chronic congestive heart failure (CHF) and systolic dysfunction. BACKGROUND Peak VO2 is an objective marker of functional capacity and is routinely used as a criterion to identify heart transplant candidates. Diastolic dysfunction limits functional capacity, but its prognostic importance relative to that of peak VO2 is unknown. METHODS Peak VO2 and mitral inflow velocities were prospectively measured in 311 consecutive patients (mean age 54 years, 84% male) with impaired left ventricular function (ejection fraction <40%; 88 patients with ischemic and 223 with dilated cardiomyopathy) who were evaluated for heart transplant candidacy. RESULTS During a mean follow-up period of 512 +/- 314 days, 65 patients died and 43 patients underwent heart transplantation. Diastolic filling patterns, peak VO2 and left ventricular end-diastolic diameters were independent predictors of cardiac mortality. In patients with peak VO2 < or = 14 ml/min per kg body weight, the outcome was markedly poorer in the presence of restrictive filling patterns as compared with their absence (two-year survival rate 52% vs. 80%). Similarly, despite peak VO2 levels >14 ml/min per kg, the outcome was less favorable in the presence of restrictive filling patterns (two-year survival rate 80% vs. 94%). A risk-stratification model based on the identified independent noninvasive predictors separated groups into those with high (93%), intermediate (65%) and low (39%) two-year survival rates. CONCLUSIONS Transmitral flow patterns add incremental value to peak VO2 in determining the prognosis of patients with CHF and impaired systolic function.

Rate- and Site-Dependent Effects of Propafenone, Dofetilide, and the New IKs-Blocking Agent Chromanol 293b on Individual Muscle Layers of the Intact Canine Heart

BACKGROUND Recent in vitro studies have demonstrated regional differences in electrophysiological properties of individual left ventricular muscle layers. Controversy exists on the relevance of these findings for the situation in vivo. Thus, this study was designed to determine whether the in vivo canine heart exhibits regional differences in left ventricular refractoriness and in the susceptibility to sodium and potassium channel blockers. METHODS AND RESULTS In 16 dogs, 36 needle electrodes (12 mm long, 4 bipolar electrodes, interelectrode distance 2.5 mm) were inserted into the left ventricular wall. By use of a computerized multiplexer-mapping system, the spread of activation in epicardial, endocardial, and midmyocardial muscle was reconstructed during ventricular pacing at 300- and 850-ms basic cycle length (BCL). Effective refractory periods (ERPs) were determined at baseline and after application of propafenone (2 mg/kg), dofetilide (30 microg/kg), or chromanol 293b (10 mg/kg) by the extrastimulus technique (BCL 300 and 850 ms). At baseline, activation patterns and ERPs were uniform in all muscle layers. Propafenone homogeneously decreased conduction velocity and moderately prolonged ERPs without any regional differences. Dofetilide and chromanol 293b did not affect the spread of activation. Dofetilide exhibited reverse use-dependent effects on ERP, still preserving transmural homogeneity of refractoriness. Chromanol 293b led to a regionally uniform but more pronounced increase in local ERPs at faster than at slower pacing rates. CONCLUSIONS At the heart rates applied, the in vivo canine heart does not exhibit regional differences in electrophysiological properties. Given the homogeneity of antiarrhythmic drug effects, induction of local gradients of refractoriness is obviously not a common mechanism of proarrhythmia in normal hearts.

Myocardial left ventricular dysfunction in patients with systemic lupus erythematosus: new insights from tissue Doppler and strain imaging.

Objective. Systemic lupus erythematosus (SLE) is associated with high cardiovascular morbidity and mortality. Cardiovascular involvement is frequently underestimated by routine imaging techniques. Our aim was to determine if new echocardiographic imaging modalities like tissue Doppler (TDI), strain rate (SRR), and strain (SRI) imaging detect abnormalities in left ventricular (LV) function in asymptomatic patients with SLE. Methods. Sixty-seven young patients with SLE (mean age 42 ± 10 yrs) without typical symptoms or signs of heart failure or angina, and a matched healthy control group (n = 40), underwent standard transthoracic echocardiography, TDI, SRR, and SRI imaging of the LV as well as assessment of disease characteristics. Results. Despite findings within the normal range on routine standard 2-dimensional echocardiography, SLE was associated with significantly impaired systolic and diastolic myocardial velocities of the LV measured by TDI [mean global TDI: systolic (s): 2.9 ± 0.9 vs 3.9 ± 0.7 cm/s, p < 0.05; early (e): 4.3 ± 1.5 vs 6.3 ± 1.3 cm/s, p < 0.05; late (a): 2.9 ± 0.8 vs 3.4 ± 0.8 cm/s, p < 0.05; values ± SD); SRR (s: −0.8 ± 0.1 vs −1.1 ± 0.1 s−1; e: 1.1 ± 0.2 vs 1.6 ± 0.3 s−1; a: 0.7 ± 0.1 vs 1.0 ± 0.2 s−1; all p < 0.05); and SR (−15.11 ± 2.2% vs −19.7 ± 1.9%; p < 0.05) compared to the control group. Further, elevated disease activity, measured with the ECLAM and the SLEDAI score, resulted in significantly lower values for LV longitudinal function measured by SRR and SR, but not by TDI. Conclusion. SLE is associated with a significant impairment of systolic and diastolic LV longitudinal function in patients without cardiac symptoms. New imaging modalities provide earlier insight into cardiovascular involvement in SLE and seem to be superior to standard echocardiography to detect subclinical myocardial disease.

Regenerative capacity of intravenous autologous, allogeneic and human mesenchymal stem cells in the infarcted pig myocardium – complicated by myocardial tumor formation

Objectives. Intravenous delivery of mesenchymal stem cells (MSCs) is an attractive approach for regeneration of infarcted myocardium. However, its efficacy is not well-defined in large animals. Methods. Pigs (n =8) received intravenously autologous, allogeneic porcine or human MSCs (1×106 per kg bodyweight) labeled with fluorescent dye 48 hours post proximal LAD occlusion. Infarct size, histology and myocardial function were assessed 4 weeks later. Results. Labeled MSCs migrated in the peri-infarct region resulting in improved myocardial function. Infarct size was larger in the control group (32±7%) compared to autologous (19±7%, p =0.008), allogeneic (24±4%, p =0.01) and human MSCs (26±5%, p =0.03). Fractional area shortening significantly increased after 4 weeks in pigs receiving autologous MSCs (34±7%, p =0.001), allogeneic MSCs (28±2%, p =0.004) and human MSCs (24±5%, p =0.027), but was lower in the control group (23±3%, n.s.). However, substantial callus formation and a non-malignant cardiac “tumor” containing mesenchymal tissue was observed in one animal treated with human MSCs. Conclusions. Intravenously administered MSCs prevent pathologic remodeling and scar formation but bare potential risks from inflammatory-related products.

Echocardiographic quantification of left ventricular asynergy in coronary artery disease with Fourier phase imaging.

Background: Visual evaluation of wall motion is subjective and may be difficult in patients with impaired left ventricular function. Current algorithms used to analyze wall motion usually neglect motion asynchrony that may be profoundly altered in coronary artery disease. This study was to investigate whether the extent of left ventricular asynergy can be used to quantify the severity of regional myocardial dysfunction by the use of Fourier phase imaging. Methods: Echocardiographic cine loops of 21 patients with ischemic cardiomyopathy (EF ≤ 40%) were mathematically transformed using a first-harmonic Fourier algorithm displaying the sequence of wall motion as phase angles in parametric images and regional phase histograms. Segmental fractional area shortening (FAC) and qualitative assessment of regional wall motion based on visual inspection served as reference method. Results: There was an inverse linear relationship between FAC and phase angles (r = −0.75, p < 0.01). Normal endocardial motion yielded low phase angles (mean 16 ± 15° SD). With an increase in wall motion abnormalities, phase angles were progressively delayed by 56 ± 38° in hypokinetic, by 88 ± 38° in akinetic, and by 143 ± 33° (p < 0.001) in dyskinetic segments. Conclusions: These results demonstrate that left ventricular asynchrony is an indicator of regional myocardial dysfunction in coronary artery disease. Echocardiographic Fourier phase imaging can be used to quantify wall motion displaying contraction sequence in a simple and objective format.

Caught in the act: entrapped embolus through a patent foramen ovale

A patent foramen ovale (PFO) is detected frequently by transesophageal echocardiography. The diagnosis of paradoxical embolism is usually presumptive when arterial emboli occur in the appropriate clinical setting. Presumably, paradoxical embolism of small thrombi arise in the venous system and pass through the PFO during a transient right-to-left shunt; however, cases demonstrating a thrombus traversing the PFO are relatively few.

Evaluation Cardioprotective Effects of Atorvastatin in Rats by Real Time Myocardial Contrast Echocardiography

Background: The ability to assess myocardial perfusion in small animals is important, especially to investigate models of myocardial ischemia. Myocardial perfusion is usually assessed by postmortem techniques, eliminating the possibility of follow‐up in intervention studies. The purpose of the study was to examine the feasibility of real time myocardial contrast echocardiography (MCE) to evaluate cardioprotective effects of atorvastatin in a rat model of acute ischemia‐reperfusion injury. Methods: The rats (n=15) underwent 20 minutes of mechanical left descending coronary artery (LAD) occlusion followed by 180 minutes of reperfusion. The animals received either atorvastatin (10 mg/kg), atorvastatin and the nitric oxide synthase (NOS)‐inhibitor N‐Nitro‐L‐Argininemethylester (L‐NAME) (15 mg/kg), or vehicle. MCE was performed to assess the size of the perfusion defect and the myocardial signal intensities (Amax) at the baseline, during occlusion, and during reperfusion. For comparison, the infarct size, risk area, and regional myocardial blood flow (MBF) were determined by the standard techniques as well. Results: The dynamics of ischemia‐reperfusion injury could be visualized serially by MCE. The infarct size‐to‐risk area ratio progressively increased during reperfusion and was markedly reduced in the atorvastatin group. Triphenyltetrazolium chloride (TTC) staining confirmed a 23% reduction in the infarct size by atorvastatin. The infarct size by MCE correlated well with the histological methods (r=0.86, P < 0.001). Amax was reduced in the anterior segments during LAD occlusion (0.08 ± 0.01 dB) compared to the baseline (2.9 ± 0.4 dB), approached higher levels post revascularization of LAD (3.22 ± 0.50 dB), but decreased during 180 minutes of reperfusion (2.32 ± 0.40 dB). After 180 minutes of reperfusion, Amax in the risk area was significantly higher in the atorvastain‐treated group compared to the vehicle‐treated group (2.32 ± 0.40 dB vs 1.3 ± 0.4 dB, P ≤ 0.05), indicating preserved MBF. The L‐NAME‐treated group showed no significant difference compared to the vehicle‐treated group (Amax 1.12 ± 0.60 dB vs 1.3 ± 0.4 dB). The regional blood flow ratio (ischemic‐to‐nonischemic wall) measured by the microspheres was significantly higher in the atorvastatin group compared to the control and the L‐NAME groups, respectively (0.92 ± 0.13 vs 0.45 ± 0.23 vs 0.51 ± 0.16, P ≤ 0.05). Conclusions: Atorvastatin has cardioprotective effects in acute reperfusion injury. Contrast echocardiography allows visual and quantitative evaluation of the dynamics of myocardial ischemia‐reperfusion injury and can be used to monitor cardioprotective effects during pharmacological interventions even in small animals.

Fourier phase and amplitude analysis for automated objective evaluation of myocardial contrast echocardiograms.

Aims: Objective methods for evaluating myocardial contrast echocardiography (MCE) are not yet widely available. We applied a Fourier analysis to myocardial contrast echocardiograms to identify myocardial perfusion defects. Methods: Harmonic power-Doppler contrast echocardiograms were performed in 21 patients undergoing Tl-201-SPECT imaging and in 13 controls. Images were transformed using Fourier analysis to obtain phase of the first harmonic sinusoidal curve displayed as color coded sequence of myocardial intensity changes. Means and standard deviations of regional phase angles were measured. The method was validated in an in vitro model. A contrast filled latex balloon was imaged at different gain settings mimicking defined time–intensity curves. An intraoperative porcine infarction model served to prove feasibility of Fourier transformation to analyze real-time pulse inversion contrast echocardiography. Results: In patients, phase imaging and intensity analysis showed focal areas with marked phase shifts (106 ± 90°) and heterogeneous distribution of phase angles (SD 66 ± 17°), correctly identifying 13/14 perfusion defects. The in vitro validation yielded increasing phase angles with increasing β-values. This method was successfully applied to real-time MCE, identifying all infarction areas during occlusion of the left anterior descending artery. Conclusion: Phase analysis can be used to display dynamics of myocardial opacification.

Usefulness of myocardial parametric imaging to evaluate myocardial viability in experimental and in clinical studies

Objective: To evaluate whether myocardial parametric imaging (MPI) is superior to visual assessment for the evaluation of myocardial viability. Methods and results: Myocardial contrast echocardiography (MCE) was assessed in 11 pigs before, during, and after left anterior descending coronary artery occlusion and in 32 patients with ischaemic heart disease by using intravenous SonoVue administration. In experimental studies perfusion defect area assessment by MPI was compared with visually guided perfusion defect planimetry. Histological assessment of necrotic tissue was the standard reference. In clinical studies viability was assessed on a segmental level by (1) visual analysis of myocardial opacification; (2) quantitative estimation of myocardial blood flow in regions of interest; and (3) MPI. Functional recovery between three and six months after revascularisation was the standard reference. In experimental studies, compared with visually guided perfusion defect planimetry, planimetric assessment of infarct size by MPI correlated more significantly with histology (r2  =  0.92 versus r2  =  0.56) and had a lower intraobserver variability (4% v 15%, p < 0.05). In clinical studies, MPI had higher specificity (66% v 43%, p < 0.05) than visual MCE and good accuracy (81%) for viability detection. It was less time consuming (3.4 (1.6) v 9.2 (2.4) minutes per image, p < 0.05) than quantitative blood flow estimation by regions of interest and increased the agreement between observers interpreting myocardial perfusion (κ  =  0.87 v κ  =  0.75, p < 0.05). Conclusion: MPI is useful for the evaluation of myocardial viability both in animals and in patients. It is less time consuming than quantification analysis by regions of interest and less observer dependent than visual analysis. Thus, strategies incorporating this technique may be valuable for the evaluation of myocardial viability in clinical routine.

Detection of acute myocardial ischemia during pharmacological stress in graded coronary artery stenosis: analysis of left ventricular asynchrony using Fourier phase imaging in pigs.

Background: Stress echocardiography is increasingly used to identify coronary artery disease, but quantitative techniques are required to improve the accuracy of this method. Current algorithms used to analyze wall motion usually neglect motion asynchrony that is found in acute ischemia. Fourier phase imaging of echocardiographic images may offer the possibility to detect asynchrony, but its feasibility with dobutamine stress echocardiography (DSE) is undefined. The aim of this study was to investigate whether the extent of left ventricular asynergy can be used to quantify the severity of regional myocardial dysfunction and to detect functionally significant coronary artery stenoses during DSE. Methods: Regional wall motion abnormalities were induced by graded coronary stenoses (mild and severe) of the left anterior descending coronary artery (LAD) in seven open-chest anesthetized pigs. DSE (10–40 μg/kg/min) was performed under control conditions and during sustained ischemia. Coronary flow was measured under resting conditions and during maximal hyperemic response due to intravenous infusion of adenosine. Functional significance of stenoses was defined as mild when coronary flow reserve (CFR) was reduced but > 1.5 and severe when CFR was ≤ 1.5. Echocardiographic cine loops were mathematically transformed using a first-harmonic Fourier algorithm displaying the sequence of wall motion as phase angles in parametric images and regional phase histograms. The phase difference (PD) of the first Fourier harmonic of posterior vs. anterior myocardial wall motion was calculated as an index of left ventricular asynchrony. Segmental fractional area shortening (FAS) and wall thickening (WT) as ratio of stress to rest served as a reference method of regional wall motion. Results: The increase in FAS (1.62 ± 0.6 vs. 0.42 ± 0.2, p = 0.0002) and WT (1.92 ± 0.5 to 0.3 ± 1.1; p = 0.004) in anterior regions during DSE was significantly higher in the control group compared to severe ischemia but not compared to mild ischemia. During graded ischemia, profiles of phase angles were consistently modified, showing a delayed onset in regional contraction. The mean PD during DSE in the control group was 10.4 ± 7°. PD rose in mild ischemic segments (CFR>1.5) to 28.9 ± 10° (p = 0.003) and to 89.6 ± 25° (p = 0.0002) in severely ischemic segments (CFR ≤ 1.5). There was a significant inverse correlation between the PDs and WT (r = −0.87, p < 0.0001). Normal WT ratios yielded low phase angles while segmental phase angles increased with decreased WT. The intraobserver variability of phase analysis was 2.7 ± 24° (mean ± 2SD). Conclusions: These results suggest that left ventricular asynchrony is an indicator of acute ischemia. Echocardiographic Fourier phase imaging is feasible to quantify wall motion displaying contraction sequence in a simple and objective format and is a␣promising approach for the clinical interpretation of stress echocardiograms.