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Preventive cardiology encompasses the whole spectrum of cardiovascular disease (CVD) prevention, at individual and population level, through all stages of life. This includes promotion of cardiovascular (CV) health, management of individuals at risk of developing CVD, and management of patients with established CVD, through interdisciplinary care in different settings. Preventive cardiology addresses all aspects of CV health in the context of the social determinants of health, including physical activity, exercise, sports, nutrition, weight management, smoking cessation, psychosocial factors and behavioural change, environmental, genetic and biological risk factors, and CV protective medications. This is the first European Core Curriculum for Preventive Cardiology, which will help to standardize, structure, deliver, and evaluate training in preventive cardiology across Europe. It will be the basis for dedicated fellowship programmes and a European Society of Preventive Cardiology (EAPC) subspecialty certification for cardiologists, with the intention to improve quality and outcome in CVD prevention., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Although cardiovascular rehabilitation (CR) is well accepted in general, CR-attendance and delivery still considerably vary between the European countries. Moreover, clinical and prognostic effects of CR are not well established for a variety of cardiovascular diseases., Methods: The guidelines address all aspects of CR including indications, contents and delivery. By processing the guidelines, every step was externally supervised and moderated by independent members of the " Association of the Scientific Medical Societies in Germany" (AWMF). Four meta-analyses were performed to evaluate the prognostic effect of CR after acute coronary syndrome (ACS), after coronary bypass grafting (CABG), in patients with severe chronic systolic heart failure (HFrEF), and to define the effect of psychological interventions during CR. All other indications for CR-delivery were based on a predefined semi-structured literature search and recommendations were established by a formal consenting process including all medical societies involved in guideline generation., Results: Multidisciplinary CR is associated with a significant reduction in all-cause mortality in patients after ACS and after CABG, whereas HFrEF-patients (left ventricular ejection fraction <40%) especially benefit in terms of exercise capacity and health-related quality of life. Patients with other cardiovascular diseases also benefit from CR-participation, but the scientific evidence is less clear. There is increasing evidence that the beneficial effect of CR strongly depends on "treatment intensity" including medical supervision, treatment of cardiovascular risk factors, information and education, and a minimum of individually adapted exercise volume. Additional psychologic interventions should be performed on the basis of individual needs., Conclusions: These guidelines reinforce the substantial benefit of CR in specific clinical indications, but also describe remaining deficits in CR-delivery in clinical practice as well as in CR-science with respect to methodology and presentation.

Current algorithms for assessing risk of atherosclerotic cardiovascular disease (ASCVD) and, in particular, the reliance on low-density lipoprotein (LDL) cholesterol in conditions where this measurement is discordant with apoB and LDL-particle concentrations fail to identify a sizeable part of the population at high risk for adverse cardiovascular events. This results in missed opportunities for ASCVD prevention, most notably in those with metabolic syndrome, prediabetes, and diabetes. There is substantial evidence that accumulation of ectopic fat and associated metabolic traits are markers for and pathogenic components of high-risk atherosclerosis. Conceptually, the subset of advanced lesions in high-risk atherosclerosis that triggers vascular complications is closely related to a set of coordinated high-risk traits clustering around a distinct metabolic phenotype. A key feature of this phenotype is accumulation of ectopic fat, which, coupled with age-related muscle loss, creates a milieu conducive for the development of ASCVD: atherogenic dyslipidemia, nonresolving inflammation, endothelial dysfunction, hyperinsulinemia, and impaired fibrinolysis. Sustained vascular inflammation, a hallmark of high-risk atherosclerosis, impairs plaque stabilization in this phenotype. This review describes how metabolic and inflammatory processes that are promoted in large measure by ectopic adiposity, as opposed to subcutaneous adipose tissue, relate to the pathogenesis of high-risk atherosclerosis. Clinical biomarkers indicative of these processes provide incremental information to standard risk factor algorithms and advanced lipid testing identifies atherogenic lipoprotein patterns that are below the discrimination level of standard lipid testing. This has the potential to enable improved identification of high-risk patients who are candidates for therapeutic interventions aimed at prevention of ASCVD.

Despite major efforts to reduce atherosclerotic cardiovascular disease (ASCVD) burden with conventional risk factor control, significant residual risk remains. Recent evidence on non-traditional determinants of cardiometabolic health has advanced our understanding of lifestyle-disease interactions. Chronic exposure to environmental stressors like poor diet quality, sedentarism, ambient air pollution and noise, sleep deprivation and psychosocial stress affect numerous traditional and non-traditional intermediary pathways related to ASCVD. These include body composition, cardiorespiratory fitness, muscle strength and functionality and the intestinal microbiome, which are increasingly recognized as major determinants of cardiovascular health. Evidence points to partially overlapping mechanisms, including effects on inflammatory and nutrient sensing pathways, endocrine signalling, autonomic function and autophagy. Of particular relevance is the potential of low-risk lifestyle factors to impact on plaque vulnerability through altered adipose tissue and skeletal muscle phenotype and secretome. Collectively, low-risk lifestyle factors cause a set of phenotypic adaptations shifting tissue cross-talk from a proinflammatory milieu conducive for high-risk atherosclerosis to an anti-atherogenic milieu. The ketone body ß-hydroxybutyrate, through inhibition of the NLRP-3 inflammasome, is likely to be an intermediary for many of these observed benefits. Adhering to low-risk lifestyle factors adds to the prognostic value of optimal risk factor management, and benefit occurs even when the impact on conventional risk markers is discouragingly minimal or not present. The aims of this review are (a) to discuss novel lifestyle risk factors and their underlying biochemical principles and (b) to provide new perspectives on potentially more feasible recommendations to improve long-term adherence to low-risk lifestyle factors.

Imaging of subclinical atherosclerosis is an integrated component of a preventive medicine algorithm; i.e. on the basis of a cardiovascular risk stratification patients with a low and intermediate risk qualify for further imaging (cave: Bayes' theorem). Imaging procedures for subclinical atherosclerosis have one thing in common: atherosclerosis is detected and localized directly, for which cardiac multidetector computed tomography (MDCT; coronary calcium scoring, CACS) and vascular ultrasound (carotid and/or femoral arteries) are used to measure the plaque burden. The result is viewed as a risk modifier. The risk assessment is not related to symptoms. In addition to the detection and localization of atherosclerosis this also enables assessment of the "risk age" according to the tables of the European Society of Cardiology (ESC) and even the biological age, which can be estimated based on nomograms. This knowledge can be used to promote patient compliance and adherence to medication.

Guidelines for prevention of cardiovascular diseases use risk scores to guide the intensity of treatment. A comparison of these scores in a German population has not been performed. We have evaluated the correlation, discrimination and calibration of ten commonly used risk equations in primary care in 4044 participants of the DETECT (Diabetes and Cardiovascular Risk Evaluation: Targets and Essential Data for Commitment of Treatment) study. The risk equations correlate well with each other. All risk equations have a similar discriminatory power. Absolute risks differ widely, in part due to the components of clinical endpoints predicted: The risk equations produced median risks between 8.4% and 2.0%. With three out of 10 risk scores calculated and observed risks well coincided. At a risk threshold of 10 percent in 10 years, the ACC/AHA atherosclerotic cardiovascular disease (ASCVD) equation has a sensitivity to identify future CVD events of approximately 80%, with the highest specificity (69%) and positive predictive value (17%) among all the equations. Due to the most precise calibration over a wide range of risks, the large age range covered and the combined endpoint including non-fatal and fatal events, the ASCVD equation provides valid risk prediction for primary prevention in Germany.

Cardiovascular (CV) risk prediction has a central role in primary CV prevention. Several risk charts have been developed in the attempt to identify subjects at risk who might benefit from more aggressive interventions. However, risk charts show main limitations and they remain underutilized in general practice. The addition of novel risk markers has substantially failed to improve risk charts discrimination power. Imaging has recently gained relevance in CV risk stratification for its ability to detect subclinical atherosclerosis. Although extending non-invasive imaging to all asymptomatic middle-aged people is currently not recommended, its progressive spread may provide information on preclinical atherosclerosis and detection of de facto initial disease might overcome some limitations of conventional risk stratification charts.

Background: Prognostication of congestive heart failure post-myocardial infarction (MI) is important for decision making. We sought of a head-to-head comparison between the prognostic implication of clinical, cardiopulmonary, and left ventricular (LV) function assessment., Methods: Retrospectively, 100 consecutive post-MI patients (MI history 1418+/-1668 days ago) were stratified by NYHA functional classification system, cardiopulmonary exercise testing (CPX) [oxygen consumption at maximal exercise (VO(2max)) and at the anaerobic threshold (VO(2AT)) resulting in the Weber classification], and LV function analysis by M-mode and two-dimensional echocardiography [LV end-diastolic and -systolic diameter index (LVDDI and LVSDI), shortening fraction (%D), and LV end-diastolic and -systolic volume index (EDVI and ESVI), LV ejection fraction (EF)]. Patients were controlled by phone call 1470+/-607 days later., Results: There was only a modest correlation between NYHA and Weber classes (r=0.402) and no correlation between VO(2max) and ESVI (r=0.080) nor between NYHA and ESVI (r=0.174). Several parameters (ESVI, LVDDI, LVSDI, %D) could discriminate NYHA classes to a higher significance (p=0.05; 0.0008; 0.0002; 0.04) than the Weber classes (n.s.; p=0.03; n.s.; n.s.). The following parameters could significantly differentiate quartiles in a log-rank analysis (Kaplan-Meier survival curves): NYHA classes (p=0.0001), Weber classes (p=0.069), EDVI (p=0.004), ESVI (p=0.0001), EF (p=0.002), LVDDI (p=0.002), LVSDI (p<0.001) and %D (p<0.001). Multivariate analysis isolated the following three parameters implying decreasing, independent prognostic information: NYHA classes (p=0.001), ESVI (p=0.003), and Weber classes (p=0.040)., Conclusions: In post-MI patients the thorough clinical assessment according the NYHA functional classification system implies higher prognostic information than more objective measures. This should be considered especially in primary care and should lessen the dependence on costly and expertise-dependent technical investigations.

In myocardial contrast echocardiography (MCE), power modulation technique may quantify myocardial perfusion in real-time. However, constant infusion of the contrast agent (CA) complicates handling. This pilot study sought for the clinical feasibility of quantitative MCE by a CA bolus application during Adenosine stress echocardiography to diagnose coronary artery disease (CAD). Twenty-four consecutive patients (pts) with contemporary coronary angiography underwent rest and maximum Adenosine stress. Signal intensity could be calculated in 316/348 left ventricular (LV) segments (91%) (18-segment model). At rest, gamma-variate (alpha) as well as saturation function (beta) was not significantly different in healthy men (n = 268) as well as CAD pts (n = 48) (alpha: 0.34 s(-1) versus 0.40 s(-1), n.s.; beta: 0.31 s(-1) versus 0.35 s(-1), n.s.). During Adenosine infusion both values increased in healthy men (alpha: 0.34 +/- 0.37 s(-1) versus 0.44 +/- 0.45 s(-1), p < 0.05; beta: 0.31 +/- 0.33 s(-1) versus 0.40 +/- 0.40 s(-1), p < 0.01), but not in CAD (alpha: 0.40 +/- 0.35 s(-1) versus 0.29 +/- 0.29 s(-1), n.s.; beta: 0.35 +/- 0.32 s(-1) versus 0.27 +/- 0.30 s(-1), n.s.). Sensitivity of alpha/beta reserve

Real-time myocardial contrast echocardiography (MCE) is a noninvasive perfusion imaging method, whereas technical and resolution problems impair its application in small animals. Hence, we investigated the feasibility of MCE in experimental cardiovascular set-ups involving healthy and infarcted myocardium in rats. Twenty-five male Wistar rats were examined under volatile anesthesia (2.5% isoflurane) with high-resolution conventional 2-D echocardiography (2DE) and real-time MCE (Sonos 7,500 with 15MHz-transducer, Philips Medical Systems, Andover, MA, USA) in short-axis view. Contrast agent (SonoVue, Bracco, Milan, Italy) was infused as a bolus into a sublingual vein. Background-subtracted contrast signal intensity (SI) was measured off-line in six end-systolic segments and fitted to an exponential curve (gamma variate). Derived peak SI was subsequently calculated and compared with wall motion and common functional measured quantities (left ventricular end-diastolic diameter [LVEDD], area shortening [AS]). Recordings were performed before and 14 days after left anterior descending (LAD) ligature. Infarction induced anterior wall motion abnormalities (WMA) in all animals (16 akinetic, 9 hypokinetic), increased LVEDD (9.1 +/- 0.6 vs. 7.9 +/- 0.6 mm, p < 0.001), reduced AS (36.1 +/- 10.0 vs. 59.5 +/- 4.1%, p < 0.001) and reduced anterior segmental SI (0.4 +/- 0.4 dB akinetic / 1.7 +/- 1.7 dB hypokinetic vs. 15.8 +/- 10.9 dB preinfarct, p < 0.001 / p < 0.001). Segmental SI in normokinetic segments remained unchanged. Area at risk (perfusion defect) correlated well with WMA (r = 0.838). These data confirmed high-resolution real-time MCE as a rational tool for assessing myocardial perfusion of Wistar rats. It may therefore be a useful diagnostic tool for in-vivo cardiovascular research in small animals.

Objectives: Dobutamine stress echocardiography (DSE) and contrast-enhanced electron beam tomography (EBCT) both have the potential to noninvasively detect coronary artery disease (CAD). We compared the accuracy of both methods to detect significant CAD in a direct comparison., Methods: 79 patients (32 women, 47 men, mean age 62 years) who were admitted for coronary angiography due to suspected CAD were studied. By EBCT coronary calcification (CAC) as well as angiography (CTA) was assessed. Presence of significant CAD was assumed if the calcium score exceeded 400 or the contrast-enhanced images displayed significant lumen reduction. DSE was performed using a standard protocol (5-40 microg/kg/min dobutamine plus 0.25-1.0 mg atropine if necessary). DSE and EBCT were independently evaluated concerning the presence of significant CAD. Results were compared to invasive, quantitative coronary angiography., Results: 6 patients (8%) in DSE and 2 patients (3%) in EBCT were unevaluable for various reasons and therefore excluded from further analysis. In the remaining 71 patients, 33 patients (46%) showed significant CAD. DSE demonstrated a sensitivity of 70% (23/33) and a specificity of 84% (32/38). EBCT showed a sensitivity of 91% (30/33) and a specificity of 74% (28/38). By combining DSE and EBCT sensitivity increased to 97% with a specificity of 63%., Conclusions: In a blinded comparison, DSE demonstrated lower sensitivity but higher specificity than EBCT for the detection of significant CAD. Sensitivity was improved by combining both modalities., (Copyright 2007 S. Karger AG, Basel.)

Objective: Transthoracic echocardiography has been employed to assess left ventricular dimensions and function in small animals. The aim of this study was to identify the limits of transthoracic echocardiography in a commonly used Wistar rat model by assessing intraobserver variability, interobserver variability, and day-to-day variability of examinations implying registrations and measurements., Methods: Twenty male adult Wistar rats (body weight 496+/-52 g) were examined under volatile isoflurane anesthesia (heart rate 302+/-26 bpm) by transthoracic echocardiography (Sonos 7500; Philips) with a 15 MHz-transducer. For calculation of intraobserver variability, examinations were repeated by the same examiner and for interobserver variability, examinations were performed independently by two investigators. For day-to-day variability, examinations were repeated 14 days later. Left ventricular diameters and areas were analyzed in parasternal short axis and in a modified parasternal long axis. Fractional shortening, area shortening, ejection fraction, stroke volume, and cardiac output were calculated., Results: Left ventricular end-diastolic diameter was 8.9+/-0.6 mm, fractional shortening 39.0+/-5.3%, area shortening 59.6+/-6.1%, ejection fraction 83.3+/-5.1%, stroke volume 0.24+/-0.06 ml, and cardiac output 72.9+/-20.6 ml/min. Intraobserver variability of left ventricular end-diastolic diameter, fractional shortening, area shortening, and ejection fraction was less than 10%, increasing to 19% for stroke volume and cardiac output. Interobserver variability of left ventricular end-diastolic diameter, fractional shortening, area shortening, ejection fraction was less than 13%, increasing to 23% for stroke volume and 25% for cardiac output. Day-to-day variability of left ventricular end-diastolic diameter, area shortening, ejection fraction was less than 11% whereas for stroke volume it was 21% and for cardiac output it was 22%. F-ratio test comparing investigated variabilities did not reveal significant differences., Conclusions: M-mode and two-dimensional echocardiography in large rats by clinically common high-end ultrasound systems can be assessed reliably. Parameters of global left ventricular performance like stroke volume and cardiac output could not be assessed with similar reliability.

Introduction: Anticoagulation in cardioversion for atrial fibrillation is performed using unfractionated heparin and oral anticoagulants. TEE-guided cardioversion, after achievement of therapeutic anticoagulation (1-3 days), may be an alternative to the traditional procedure (3-week anticoagulation followed by cardioversion). The quality of anticoagulation in atrial fibrillation has not been investigated in a randomised trial with TEE-guided cardioversion. We analysed respective data from the ACE trial on the quality of conventional anticoagulation, where most participating centres chose the TEE-guided approach., Materials and Methods: In a randomised, prospective, multicentre trial, we analysed the efficacy of unfractionated heparin plus phenprocoumon in 248 patients on an intention-to-treat basis. There were 2373 evaluable anticoagulation measurements (out of 2925 measurements) and 4 categories of anticoagulation quality (under-, target, over- and severe over-anticoagulation). Of patients with evaluable measurements, 88% received short-term anticoagulation (4 weeks) in TEE-guided cardioversion., Results: The median time to achieve therapeutic anticoagulation (aPTT> or =60 and <80 s or INR> or =2 and <3) was 3 days. Anticoagulation values were out of therapeutic range in 69.5% of measurements during 4- or 7-week follow-up, and never within therapeutic range in 10% of patients. Of the 15 primary endpoints observed (death, thromboembolism and major bleeding complications), only 3 were in patients with anticoagulation measurements within therapeutic range., Conclusions: In this study setting, with predominance of 4 weeks anticoagulation in TEE-guided cardioversion for atrial fibrillation, therapeutic anticoagulation was reached within 3 days using conventional anticoagulation. Despite careful dose adjustments, anticoagulation was out of therapeutic range in almost 70% of total measurements and 80% of primary endpoints.

Objective: To estimate, from the perspective of Statutory Health Insurance (SHI, third-party payer) in Germany, the economic consequences of using the subcutaneous low-molecular-weight heparin (LMWH) enoxaparin instead of intravenous unfractionated heparin followed by oral phenprocoumon (UFH/PPC) for anticoagulation in patients undergoing transesophageal echocardiography (TEE)-guided early electrical cardioversion (ECV) of persisting nonvalvular atrial fibrillation (AF) without intracardiac clot., Design and Setting: The incremental cost for the enoxaparin-based regimen versus the UFH/PPC-based regimen was chosen as the target variable. A decision-analytic model considering the in- and outpatient sectors was used to quantify the target variable. Resource use during in- and outpatient treatment was taken from the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial and from expert interviews with cardiologists in Germany in order to reflect the day-to-day conditions of clinical practice. Costs were given by SHI expenses for inpatient treatment and for medical services, drugs, disposables, and laboratory tests during outpatient treatment. These costs were determined by multiplying utilized resource items by the price or tariff of each item based on German healthcare regulations for the reference period of 2003/2004. According to the ACE trial, the evaluation encompassed 28 (26-30) treatment days with two consecutive phases. Phase I with 5 (3-12) days comprised diagnostics, start of anticoagulation, and ECV. Phase II with the remaining days consisted of continued anticoagulation and patient monitoring. The dosage of enoxaparin was 1 mg/kg bodyweight twice daily in treatment phase I followed by 40 mg twice daily with a bodyweight <65 kg or 60 mg twice daily with a BW > or =65 kg in treatment phase II. The daily dosages of UFH by continuous infusion and overlapping PPC were adjusted to an International Normalized Ratio of 2.0-3.0 in treatment phase I followed by 2.25mg PPC once daily in treatment phase II. Patients with any comorbidity and complication level (CCL) and those with low comorbidity and complications expected to occur in rare cases only (low-risk patients) were analyzed separately. In each base-case analysis, exclusively point estimates of all respective model parameters were applied., Main Outcome Measures and Results: There were savings of 339 euro and 579 euro per patient receiving the enoxaparin-based regimen versus the UFH/PPC-based regimen in the case of patients with any CCL and of low-risk patients, respectively (1 euro approximate, equals $US1.25; first quarter 2004 values). In comprehensive sensitivity analyzes, the robustness of the model and its results was shown. First, the impact of the model parameters on the target variable for each patient group was quantified in a deterministic model. Secondly, the dependency of the target variable on random variables was described for each patient group using Monte Carlo simulation. Irrespective of the patient group, the cost weight and the base rate of hospitals for inpatient ECV in phase I turned out to have the greatest impact on the savings obtained by the enoxaparin-based regimen. In the case of patients with any CCL, this impact was about 1.4-fold of that of the probability of enoxaparin patients undergoing outpatient ECV in phase I. In the case of low-risk patients, the impact of the cost weight and the base rate of hospitals for inpatient ECV in phase I was about 4.1-fold of that of the price of enoxaparin 60 mg prefilled syringes in the outpatient sector. In 79% and 93% of 10,000 simulated comparisons each versus the UFH/PPC-based regimen, there were savings obtained by the enoxaparin-based regimen in patients with any CCL and in low-risk patients, respectively., Conclusions: Results of this evaluation showed that an enoxaparin-based regimen for TEE-guided ECV of AF in patients without intracardiac clot offers SHI in Germany a considerable saving potential when used instead of an UFH/PPC-based regimen.

Background/aims: Mitral regurgitation (MR) following myocardial infarction (MI) may be a (sub)acute complication which independently predicts reduced survival. We sought to evaluate the chronic development of MR as potential consequence of left-ventricular (LV) remodelling, the latter being a long-term process., Methods and Results: Retrospectively, 103 post-MI patients were included according to a standardised Doppler echocardiogram <3 months following MI (20 +/- 25 days post-MI) and a follow-up examination >6 months after the first examination (5.1 +/- 3.1 years post-MI). Patients were clinically followed up for 7.6 +/- 2.7 years. Group I patients were defined as those showing new development or deterioration in one of three grades of MR, and group II those without this criterion (MR grade acute 0.17 vs. 0.27, p = 0.7, and chronic 1.53 vs. 0.19, p < 0.0001). Patient characteristics were similar in respect of age, gender, size and location of infarction. However, group I patients had coronary artery disease with more vessels involved. With regard to echocardiographic parameters of significantly enlarged LV chamber size in group I vs. group II, the significant decrease in LV performance was more pronounced and occurred concomitant with a higher degree of symptomatic congestive heart failure and greater need for heart failure medications in group I. Mortality in group I patients was 39 versus 9% in group II patients (p = 0.0002), approximating an odds ratio of 6.4697 (95% confidence interval: 2.211-18.931)., Conclusion: First of all, this retrospective study indicates that MR may be detected in patients after MI during a long-term follow-up most probably due to geometric distortions of LV remodelling resulting in a significantly higher mortality. Since this process is known to become irreversible at a certain point, serial echocardiography may help to detect MR in post-MI patients and thus pave the way for appropriate treatment., (2007 S. Karger AG, Basel)

The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1-4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.

The effect of operating parameters on the thrombolytic potency of ultrasound (US) is important for potential therapeutic applications, but is not fully understood. Fresh human whole-blood thrombi were exposed in vitro to focused US from a diagnostic transducer driven by an impulse generator via an amplifier to vary duration (10 to 60 min), intensity (7 to 90 W/cm(2)), frequency (2 to 4.5 MHz), pulsed wave duty cycle (1:5 to 1:100 and continuous wave mode) and pulse length (100 to 400 micros). Segments of thrombi (498 +/- 73 mg) were submersed and insonated in saline solution. Thrombolytic efficiency was expressed as percentage loss of mass compared with controls (noninsonified thrombi). Ultrasound exposure achieved a significantly higher thrombolysis than no US, 56 +/- 16 % vs. 29 +/- 11 % (n = 232, p < 10(-6)). There was an exponential saturation-type correlation with duration of insonation (r(2) = 0.64) and intensity (r(2) = 0.97), an inverse correlation with US frequency at matched intensities (r(2) = 0.76, p < 10(-5)), a logarithmic relationship with duty cycle in pulsed mode (r(2) = 0.86) and a modest direct effect of pulse length (r(2) = 0.57, p < 10(-5)). Thus, thrombolytic efficiency of US depends directly on duration, intensity, duty cycle and pulse length and inversely, on frequency.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting an estimated 2.2 million Americans. The management of non-valvular AF is likely to become even more challenging over the coming decades. The treatment target of AF takes 3 forms: cardioversion, rate control, and minimization of embolic risk. Recently, rate, rather than rhythm control has emerged as a valid therapeutic option in patients with persistent AF. According to current guidelines, International Normalized Ratio-targeted oral anticoagulation and proper stratification of risk remain fundamental principles of management. This article reviews, in depth, the current therapeutic options for atrial fibrillation including oral anticoagulants and unfractionated heparin, as well as reviewing new therapeutic options including bridging therapy with low-molecular-weight heparins and the new oral antithrombotic drug, ximelagatran.

Three-dimensional echocardiography (3DE) improves the accuracy of left ventricle (LV) volumetry compared with the two-dimensional echocardiography (2DE) approach because geometric assumptions in the algorithms may be eliminated. The relationship between accuracy of mode (short- versus long-axis planimetry) and the number of component images versus time required for analysis remains to be determined. Sixteen latex models simulating heterogeneously distorted (aneurysmatic) human LVs (56-303 ml; mean 182+/-82 ml) were scanned from an 'apical' position (simultaneous 2DE and 3DE). For 3DE volumetry, the slice thickness was varied for the short (C-scan) and long axes (B-scan) in 5-mm steps between 1 and 25 mm. The mean differences (true-echocardiographic volumes) were 16.5+/-44.3 ml in the 2DE approach (95% confidence intervals -27.8 to +60.8) and 0.6+/-4.0 ml (short axis; 95% confidence intervals -3.4 to +4.6) as well as 2.1+/-9.9 ml (long axis; 95% confidence intervals -7.8 to +12.0) in the 3DE approach (in both cases, the slice thickness was 1 mm). Above a slice thickness of 15 mm, the 95% confidence intervals increased steeply; in the short versus long axes, these were -6.5 to +8.5 versus -7.0 to +10.6 at 15 mm and -10.1 to +15.7 versus -11.3 to +10.9 at 20 mm. The intra-observer variance differed significantly (p<0.001) only above 15 mm (short axis). Time required for analysis derived by measuring short-axis slice thicknesses of 1, 15, and 25 mm was 58+/-16, 7+/-2 and 3+/-1 min, respectively. The most rational component image analysis for 3DE volumetry in the in vitro model uses short-axis slices with a thickness of 15 mm., (Copyright (c) 2005 S. Karger AG, Basel.)

Myocardial viability within the infarct zone is an important determinant for left ventricular (LV) function recovery after interventional coronary revascularization. Echocardiographic techniques are highly valuable in identifying hibernation, especially in conjunction with dobutamine titration. Low doses may detect the inotropic reserve by significant enhancement of segmental wall motion abnormalities while high doses may surpass the ischemic threshold and wall motion deteriorates (biphasic response). According to the Task Forces on Clinical Application of Echocardiography by the American Heart Association (AHA) in cooperation with the American College of Cardiology (ACC), dobutamine echocardiography (DE) is officially recommended for the purpose of clinical decision making in respect of revascularization therapies (whether during the subacute infarct period or especially in chronic LV dysfunction due to coronary artery disease (CAD)). New methods such as strain rate imaging implemented in DE are on the way to give us quantitative measures of the amount of viability.

Aims: To determine whether Doppler based myocardial tissue velocity imaging (TVI) or strain rate imaging (SRI) is more accurate in detecting stress-induced ischaemia during dobutamine stress echocardiography (DSE)., Methods and Results: Regional myocardial velocity, displacement, strain rate and strain patterns during DSE were investigated in 44 routine patients with known or suspected coronary artery disease. Simultaneous perfusion scintigraphy defined regional ischaemia. Curves and curved-M-mode patterns were analysed and receiver-operating-characteristics of TVI and SRI parameters were compared by their area under the curve (AUC) in the receiver-operating-characteristics. In non-ischaemic segments, peak systolic velocity and strain rate increased significantly. Unlike SRI, TVI parameters had higher values in basal than in apical segments. In 47 segments of 19 segments DSE-induced ischaemia, which was proven by scintigraphy. In ischaemia, velocity and strain rate increased less. Post-systolic shortening (PSS) was always seen in SRI but not regularly in TVI. Peak systolic velocity and systolic displacement were the best TVI-parameters of stress-induced ischaemia (AUC 0.68 and 0.77, respectively.), in SRI it was the ratio of PSS and maximal segmental deformation (AUC=0.95, p < 0.0001)., Conclusion: Compared to TVI, SRI parameters showed no major apico-basal gradient and had significantly higher diagnostic accuracy, comparable to conventional reading. SRI thus appears superior to TVI for regional ischaemia detection during DSE and may be preferred to support conventional DSE reading., (Copyright 2004 Elsevier Ltd)

Background: Anticoagulation in cardioversion of atrial fibrillation is currently performed with unfractionated heparin (UFH) and oral anticoagulants, with or without guidance by transesophageal echocardiography (TEE). Low-molecular-weight heparins may reduce the risk of bleeding, may obviate the need for intravenous access, and do not require frequent anticoagulation monitoring., Methods and Results: In a randomized, prospective multicenter trial, we compared the safety and efficacy of enoxaparin administered subcutaneously with intravenous UFH followed by the oral anticoagulant phenprocoumon in 496 patients scheduled for cardioversion of atrial fibrillation of >48 hours' and < or =1 year's duration. Patients were stratified to cardioversion with (n=431) and without (n=65) guidance by TEE. The study aimed to demonstrate noninferiority of enoxaparin compared with UFH+phenprocoumon with regard to the incidence of embolic events, all-cause death, and major bleeding complications. Secondary end points included successful cardioversion, maintenance of sinus rhythm until study end, and minor bleeding complications. Of 496 randomized patients, 428 were analyzed per protocol. Enoxaparin was noninferior to UFH+phenprocoumon with regard to the incidence of the composite primary end point in a per-protocol analysis (7 of 216 patients versus 12 of 212 patients, respectively; P=0.016) and in an intention-to-treat analysis (7 of 248 patients versus 12 of 248 patients, respectively; P=0.013). There was no significant difference between the 2 groups in the number of patients reverted to sinus rhythm., Conclusions: Enoxaparin is noninferior to UFH+phenprocoumon for prevention of ischemic and embolic events, bleeding complications, and death in TEE-guided cardioversion of atrial fibrillation. Its easier application and more stable anticoagulation may make it the preferred drug for initiation of anticoagulation in this setting.

The mode and duration of anticoagulation in the setting of cardioversion of atrial fibrillation-either with or without guidance by transesophageal echocardiography (TEE)-is still an unresolved issue. Oral anticoagulation with warfarin or phenprocoumon is frequently used but may be associated with an increased risk of bleeding complications or, conversely, episodes of undercoagulation. Moreover, it takes several days to reach full anticoagulation with oral compounds. This phase may be covered with intravenous heparin but this requires prolonged hospitalization. Low-molecular weight heparin is an attractive alternative as it not only provides a safe and predictable level of anticoagulation with few side effects but can also be administered safely on an outpatient basis. In addition, anticoagulation monitoring is usually unnecessary. The ACE study (Anticoagulation in Cardioversion using Enoxaparin) compared the safety and efficacy of subcutaneous enoxaparin with intravenous heparin/oral phenprocoumon before and after cardioversion (stratified to TEE guidance or no TEE guidance). This article summarizes the study rationale and design. The results will be published shortly.

Objective: Myocardial longitudinal shortening after aortic valve closure (postsystolic shortening [PSS]) is considered a marker of pathology with diagnostic potential. However, PSS can also occur in healthy subjects. We, therefore, investigated the occurrence and characteristics of PSS in control subjects and patients, and how to distinguish normality from disease., Methods: In 20 young control subjects, 10 older control subjects, 30 patients with acute myocardial infarction (acute ischemia), and 10 patients with postischemic myocardial scar, longitudinal myocardial deformation was measured with Doppler tissue strain rate (SR) imaging. Segmental SR and strain were visually and quantitatively analyzed and compared., Results: In young control subjects, PSS was found in 98 of 313 segments (31%) and showed gaussian distribution (median 1.3%). During ejection time, median peak SR was -1.4 s(-1) and median strain -16.6%. In older control subjects, parameters differed only slightly. In acutely ischemic and scarred myocardium, both systolic strain and SR were significantly reduced or inverted. In disease, PSS occurred significantly more often (78% and 79%, respectively), was significantly higher in magnitude, and its peak occurred later than in young and older control subjects., Conclusion: PSS is a normal finding in healthy subjects occurring in approximately one-third of myocardial segments and, thus, is not always a marker of disease. Our data indicate that pathologic PSS can be detected by coexisting reduction in systolic strain and, second, by exceeding a postsystolic strain magnitude cutoff.

Background: Interpretation of dobutamine stress echocardiography (DSE) is subjective and strongly dependent on the skills of the reader. Strain-rate imaging (SRI) by tissue Doppler may objectively analyze regional myocardial function. This study investigated SRI markers of stress-induced ischemia and analyzed their applicability in a clinical setting., Methods and Results: DSE was performed in 44 patients with known or suspected coronary artery disease. Simultaneous perfusion scintigraphy served as a "gold standard" to define regional ischemia. All patients underwent coronary angiography. Segmental strain and strain rate were analyzed at all stress levels by measuring amplitude and timing of deformation and visual curved M-mode analysis. Results were compared with conventional stress echo reading. In nonischemic segments, peak systolic strain rate increased significantly with dobutamine stress (-1.6+/-0.6 s-1 versus -3.4+/-1.4 s-1, P<0.01), whereas strain during ejection time changed only minimally (-17+/-6% versus -16+/-9%, P<0.05). During DSE, 47 myocardial segments in 19 patients developed scintigraphy-proven ischemia. Strain-rate increase (-1.6+/-0.8 s-1 versus -2.0+/-1.1 s-1, P<0.05) and strain (-16+/-7% versus -10+/-8%, P<0.05) were significantly reduced (both P<0.01 compared with nonischemic). Postsystolic shortening (PSS) was found in all ischemic segments. The ratio of PSS to maximal segmental deformation was the best quantitative parameter to identify stress-induced ischemia. Compared with conventional readings, SRI curved M-mode assessment improved sensitivity/specificity from 81%/82% to 86%/90%., Conclusions: During DSE, SRI quantitatively and qualitatively differentiates ischemic and nonischemic regional myocardial response to dobutamine stress. The ratio of PSS to maximal strain may be used as an objective marker of ischemia during DSE.

Background: Cell grafting has emerged as a novel approach to treat heart diseases refractory to conventional therapy. We hypothesize that survival and functional and electrical integration of grafts may be improved by engineering cardiac tissue constructs in vitro before grafting., Methods and Results: Engineered heart tissue (EHT) was reconstituted by mixing cardiac myocytes from neonatal Fischer 344 rats with liquid collagen type I, matrigel, and serum-containing culture medium. EHTs were designed in circular shape (inner/outer diameter: 8/10 mm; thickness: 1 mm) to fit around the circumference of hearts from syngenic rats. After 12 days in culture and before implantation on uninjured hearts, contractile function of EHT was measured under isometric conditions. Baseline twitch tension amounted to 0.34+/-0.03 mN (n=33) and was stimulated by Ca(2+) and isoprenaline to 200+/-12 and 185+/-10% of baseline values, respectively. Despite utilization of a syngenic model immunosuppression (mg/kg BW: azathioprine 2, cyclosporine A 5, methylprednisolone 2) was necessary for EHT survival in vivo. Echocardiography conducted 7, 14, and 28 days after implantation demonstrated no change in left ventricular function compared with pre-OP values (n=9). Fourteen days after implantation, EHTs were heavily vascularized and retained a well organized heart muscle structure as indicated by immunolabeling of actinin, connexin 43, and cadherins. Ultrastructural analysis demonstrated that implanted EHTs surpassed the degree of differentiation reached before implantation. Contractile function of EHT grafts was preserved in vivo., Conclusions: EHTs can be employed for tissue grafting approaches and might serve as graft material to repair diseased myocardium.

Background: Strain rate imaging is a new and intriguing way of displaying myocardial deformation properties by means of echocardiography. With high frame rate strain rate imaging we observed a spatial inhomogeneity in diastolic longitudinal strain rates in healthy persons. A base-to-apex time delay in diastolic lengthening could be seen both in early diastole and at atrial contraction., Methods and Results: We investigated this consistent finding and its dependence on loading conditions in 20 healthy volunteers. Propagation velocities of lengthening of 91 +/- 31 cm/s (E-wave) and 203 +/- 11 cm/s (A-wave) at rest (equal to time delays of 104 +/- 29 ms and 56 +/- 24 ms, respectively) increased significantly to 101 +/- 27 cm/s (E) and 283 +/- 17 cm/s (A) with lifting the volunteers' legs. Applying nitroglycerin sublingually and sitting upright significantly decreased propagation velocities (E-wave 76 +/- 20 cm/s, A-wave 172 +/- 93 cm/s and E-wave 66 +/- 17 cm/s, A-wave 150 +/- 64 cm/s, respectively). Free lateral walls showed a lower propagation velocity than septal walls., Conclusion: We conclude that the propagation velocities of left ventricular lengthening waves are dependent on preload changes and increase with increasing preload.

Tissue Doppler echocardiography (TDE) is a new method by which transmural myocardial function can be studied noninvasively. In order to investigate physiology and reproducibility, 24 young, healthy volunteers were examined by M-mode TDE. Nonuniformity of transmural tissue layer velocities became apparent: Subendocardial and subepicardial velocities of the anteroseptal myocardial wall (AW) were 3.5 +/- 0.7 and 1.3 +/- 0.5 cm/sec (P < 0.0001, t-test), whereas in the posterolateral wall (PW) values of 3.6 +/- 0.6 and 1.2 +/- 0.4 cm/sec (P < 0.0001, t-test), respectively, were revealed. The ratios, termed "myocardial velocity gradients" as a new indicator of left ventricular performance, were 3.1 +/- 1.0 and 3.4 +/- 1.1, respectively. AW and PW did not differ (N.S.). Tolerance borders did not overlap, and intraobserver variability did not reach intersubject variability (P < 0.0001, F-ratio test). TDE provides new and more sophisticated insights into left ventricular performance. It seems to be accurate and reliable and therefore worth introducing into the clinical arena.