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Objective: The goal of this study was to evaluate the very long-term outcome after normal exercise (99m)Tc-sestamibi myocardial perfusion single-photon emission computed tomography (SPECT). Exercise (99m)Tc-sestamibi SPECT is widely used for risk stratification, but data on very long-term outcome after a normal test are scarce.Methods: A consecutive group of 233 patients (122 men, mean age 54 ± 12 years) with known or suspected coronary artery disease (CAD) underwent exercise (99m)Tc-sestamibi SPECT and had normal myocardial perfusion at exercise and at rest. Follow-up endpoints were all-cause mortality, cardiac mortality, nonfatal myocardial infarction, and coronary revascularization. Predictors of outcome were identified by Cox proportional hazard regression models using clinical and exercise testing variables.Results: During a mean follow-up of 15.5 ± 4.9 years, 41 (18%) patients died, of which 13 were cardiac deaths. A total of 18 (8%) patients had a nonfatal myocardial infarction, and 47 (20%) had coronary revascularization. The annualized event rates for all-cause mortality, cardiac mortality, cardiac mortality/nonfatal infarction, and major adverse cardiac events were, respectively, 1.1%, 0.3%, 0.7%, and 1.8%. Multivariate analysis demonstrated that the variables age, male gender, diabetes, diastolic blood pressure at rest, rate pressure product at rest, peak exercise heart rate, and ST segment changes were independent predictors of major adverse cardiac events.Conclusion: Patients with suspected or known CAD and normal exercise (99m)Tc-sestamibi myocardial perfusion SPECT have a favorable 15-year prognosis. Follow-up should be closer in patients with known CAD, and/or having clinical and exercise parameters indicating higher risk status. [ABSTRACT FROM AUTHOR]

Objective: To determine the incremental prognostic value of dobutamine stress echocardiography (DSE) at 13-year follow-up (SD 3.2 years) for predicting mortality and cardiac events in diabetic patients.Research Design and Methods: A total of 396 diabetic patients (mean age 61 ± 11 years; 252 men [64%]) with limited exercise capacity who underwent DSE for evaluation of ischemia were studied. End points were all causes of mortality, cardiac death, and hard cardiac events (cardiac death and nonfatal myocardial infarction).Results: During a mean follow-up of 13 years, 230 patients (58%) died (121 cardiac deaths), and 30 patients had nonfatal myocardial infarction. Cumulative survival in patients with an abnormal DSE at 5, 10, and 15 years was 68, 49, and 41%, respectively. In patients with a normal DSE, these respective numbers were 74, 57, and 44%. Multivariate analyses showed that DSE provided incremental value over clinical characteristics and stress test parameters for prediction of mortality and cardiac events. Survival analysis showed that DSE provided optimal risk stratification up to 7 years after initial testing; after that period, the risk of adverse outcome increased comparably in both normal and abnormal DSE patients.Conclusions: DSE provided restricted predictive value of adverse outcome in patients with diabetes who were unable to perform an adequate exercise stress test. DSE provided optimal risk stratification up to 7 years after initial testing. Repeated DSE at that time might add to its prognostic value. [ABSTRACT FROM AUTHOR]

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed. [ABSTRACT FROM AUTHOR]

BACKGROUND: In patients with ischaemic cardiomyopathy and viable myocardium, left ventricular ejection fraction (LVEF) does not always improve after revascularisation. Whether this may affect prognosis is unclear. OBJECTIVE: To evaluate the prognosis of viable patients with and without improvement of LVEF after coronary revascularisation. METHODS: Before revascularisation, radionuclide ventriculography (RNV) and dobutamine stress echocardiography were performed to assess LVEF and myocardial viability, respectively. Nine to 12 months after revascularisation, LVEF improvement was assessed by RNV. Patients were divided into three groups: group 1, viable patients with LVEF improvement (n = 27); group 2, viable patients without LVEF improvement (n = 15), group 3, non-viable patients (n = 48). Cardiac events were evaluated during a 4-year follow-up. RESULTS: After revascularisation, the mean (SD) LVEF improved from 32 (9)% to 42 (10)% in group 1, but did not change significantly in group 2 and in group 3, p<0.001 by analysis of variance (ANOVA). Heart failure symptoms improved in both groups 1 (mean (SD) NYHA class from 3.1 (0.9) to 1.7 (0.7)) and 2 (from 3.2 (0.7) to 1.7 (0.9)), but not in group 3 (from 2.8 (1.0) to 2.7 (0.5)), p<0.001 by ANOVA. During follow-up, the cardiac event rate was low (4%) in group 1, intermediate (21%) in group 2 and high (33%) in group 3 (p = 0.01). CONCLUSION: The best prognosis after revascularisation may be expected in those viable patients whose LVEF improves. Conversely, viable patients without functional improvement have an intermediate prognosis. [ABSTRACT FROM AUTHOR]

Background: Repeat coronary artery bypass grafting (redo-CABG) in patients with ischaemic cardiomyopathy is associated with high perioperative risk and worse long-term outcome compared with patients undergoing their first CABG. Objective: To assess whether patients with viable myocardium undergoing redo-CABG have a better outcome. Methods: 18 patients with ischaemic cardiomyopathy underwent redo-CABG and 34 underwent their first CABG; all had substantial viability (> or =25% of the left ventricle) on dobutamine stress echocardiography (DSE). Left ventricular ejection fraction (LVEF) and heart failure symptoms were assessed before and 9-12 months after revascularisation. Cardiac event rate was assessed during the follow-up period (median 4 years, 25-75th centile 2.8-4.9 years). Results: The extent of viable myocardium on DSE was comparable in the two groups (11.3 (3.9) segments in patients who underwent redo-CABG v 12.8 (3.0) in patients who underwent their first CABG; p = NS). LVEF improved from 32% (9%) to 39% (12%); p = 0.01, in patients who underwent redo-CABG and from 30% (7%) to 36% (7%); p<0.01, in those who underwent their first CABG; New York Heart Association class improved from 2.5 (1.1) to 1.9 (0.8); p = 0.03, and from 2.7 (1.0) to 1.8 (0.70); p<0.01, respectively. In patients who underwent redo-CABG, the perioperative mortality was 0, post-surgery inotropic support was needed in 11% of the patients and mid-term (4-year) survival was 100%, with a total event rate of 28%. All these variables were not statistically different from patients who underwent their first CABG (p = 0.50, 0.90, 0.08 and 0.81, respectively). Conclusion: Patients with ischaemic cardiomyopathy and substantial viability undergoing redo-CABG benefit from revascularisation in terms of improvement in LVEF, heart failure symptoms, angina and mid-term prognosis. [ABSTRACT FROM AUTHOR]

The present study describes the presence of pseudoenhancement during contrast-enhanced ultrasound (CEUS) imaging of human carotid arteries and the reproduction of this pseudoenhancement in vitro. Seventy patients underwent bilateral CEUS examination of the carotid arteries using a Philips iU22 ultrasound system equipped with a L9-3 ultrasound probe and SonoVue microbubble contrast. During CEUS of the carotid arteries, we identified enhancement in close proximity to the far wall, parallel to the main lumen. The location of this enhancement does not correlate to the anatomical location of a parallel vessel. To corroborate the hypothesis that this is a pseudoenhancement artifact, the enhancement was recreated in a tissue-mimicking material phantom, using the same ultrasound system, settings and contrast agent as the patient study. The phantom study showed that pseudoenhancement may be present during vascular CEUS and that the degree of pseudoenhancement is influenced by the size and concentration of the microbubbles. During vascular CEUS, identification of the artifact is important to prevent misinterpretation of enhancement in and near the far wall. [ABSTRACT FROM AUTHOR]

The clinical utility of stress testing in patients without angina pectoris after revascularization has been questioned. Dobutamine stress echocardiography (DSE) is an established technique for detection of myocardial ischemia and cardiac risk stratification. We studied the prognostic value of DSE in 393 patients without typical angina pectoris after coronary revascularization. Ischemia was incremental to clinical data in predicting all-cause death (hazard ratio 3.5, 95% confidence interval 1.8 to 6.7) and cardiac death (hazard ratio 4.2, 95% confidence interval 1.8 to 9.8). In conclusion, myocardial ischemia during DSE is independently associated with an increased risk of all-cause mortality and cardiac death in these patients after adjustment for clinical data. [ABSTRACT FROM AUTHOR]

The etiology of chest pain in hypertrophic cardiomyopathy (HC) is diverse and includes coronary artery disease (CAD) as well as HC-specific causes. Myocardial bridging (MB) has been associated with HC, chest pain, and accelerated atherosclerosis. We compared HC patients with age-, gender- and CAD pre-test probability-matched outpatients presenting with chest pain to investigate differences in the presence of MB and CAD using coronary computed tomography angiography (CCTA). We studied 84 HC patients who underwent CCTA and compared these with 168 matched controls (age 54 ± 11 years, 70% men, pre-test probability 12% [5% to 32%]). MB, calcium score, plaque morphology and presence and extent of CAD were assessed for each patient. Linear mixed models were used to assess differences between cases and controls. MB was more often seen in HC patients (50% vs 25%, p <0.001). Calcium score and the presence of obstructive CAD were similar in both groups (9 [0 to 225] vs 4 [0 to 82] and 18% vs 19%; p = 0.22 and p = 0.82). In the HC group, MB was associated with pathogenic DNA variants (p = 0.04), but not with the presence of chest pain (74% vs 76%, p = 0.8), nor with worse outcome (log-rank p = 0.30). In conclusion, the prevalence and extent of CAD was equal among patients with and without HC, demonstrating that pre-test risk prediction using the CAD Consortium clinical risk score performs well in HC patients. MB was twice as prevalent in the HC group compared with matched controls, but was not associated with chest pain or decreased event-free survival in these patients., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The echocardiographic focus to detect abnormalities in genetically hypertrophic cardiomyopathy (HCM) affected subjects without left ventricular (LV) hypertrophy (G+/LVH-) has been on diastolic abnormalities in transmitral flow and longitudinal myocardial function with tissue Doppler imaging. The aim of this study was to assess diastolic LV unstrain and untwist., Methods and Results: Forty-one consecutive genotyped family members of HCM patients (mean age 37 ± 11 years, 16 men) and 41 age- and gender-matched healthy volunteers underwent speckle-tracking echocardiography to measure untwist and unstrain. No significant differences between G+/LVH- and control subjects were seen in maximal systolic twist and global longitudinal strain. In diastole, the early peak untwist rate was significantly lower in G+/LVH- subjects compared with control subjects (62 ± 19°s - 1 vs. 76 ± 30°s - 1, P <0.05), whereas the late peak untwist rate tended to be higher. Untwist from maximal twist until the first 20% of diastole was delayed in G+/LVH- subjects (39.3 ± 12.9% vs. 51.3 ± 15.6%, P <0.005). Late diastolic unstrain rate was significantly higher in G+/LVH- subjects in the inferoseptal wall (111 ± 33 s - 1 vs. 94 ± 32 s - 1, P = 0.024), the inferolateral wall (105 ± 42 vs. 75 ± 35 s - 1, P = 0.007) and the anteroseptal wall (97 ± 26 vs. 80 ± 23 s - 1, P = 0.010). Unstrain from maximal twist until the first 20% of diastole was delayed in G+/LVH- subjects in the inferoseptal (18.9 ± 14.0% vs. 30.1 ± 17.7%, P = 0.005), inferolateral (27.1 ± 16.3% vs. 39.2 ± 18.0%, P = 0.015) and anteroseptal (19.1 ± 14.7% vs. 35.8 ± 18.5%, P = 0.0003) segments., Conclusions: In mutation carriers, for HCM LV, untwist and unstrain are delayed and untwist rate and unstrain rate are decreased., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)

Atrial fibrillation (AF) is a common complication of hypertrophic cardiomyopathy (HC) and associated with adverse clinical outcomes, such as thromboembolisms. Cardiac implantable electronic devices (CIEDs) enable early detection of AF. The aim of this study was to assess the incidence of device-detected AF and the impact on long-term outcomes in patients with HC. The cohort consisted of 132 patients (63% men, mean age 52 ± 16 years) with a diagnosis of HC and a CIED. Follow-up started at the date of CIED implantation to assess the incidence of device-detected AF. Patients with persistent AF at the time of implantation were excluded from the analysis of the incidence of AF. End points were all-cause and cardiac mortality, device-detected AF, and thromboembolism (stroke, transient ischemic attack, or peripheral arterial embolism). In total, 114 patients were in sinus rhythm at time of CIED implantation. During the median 2.8 (interquartile range 1.2 to 5.4) years of follow-up, device-detected AF occurred in 29 patients (25%), resulting in an annual incidence of 7.0%/year. Device-detected AF led to a change in the clinical management in 22 patients (76%). Anticoagulation therapy was started in 13 (45%), antiarrhythmic medication in 9 (31%), and electrical cardioversion in 8 (28%) patients. Six patients (5%) suffered a thromboembolic complication. All-cause mortality was 27 (20%), and cardiac mortality was 21 (16%). A history of AF at time of implantation was an independent predictor of cardiac death (hazard ratio 4.7, p = 0.003). In conclusion, the incidence of device-detected AF in patients with HC was 7.0%/year, leading to a change in clinical management in the majority (76%) of cases to reduce the risk of thromboembolic complications. These findings stress the importance of AF detection in HC and advocate vigilant interrogation of the device., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background and Aims: Statins reduce subclinical atherosclerosis and premature atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH). However, some FH patients still develop ASCVD despite statin therapy. We compared subclinical atherosclerosis assessed by carotid plaque presence and intima media thickness (C-IMT), in long-term statin-treated FH patients and healthy controls. Furthermore, we analysed whether carotid ultrasonography findings associated with subclinical coronary atherosclerosis., Methods: We assessed the presence of carotid plaques and C-IMT in 221 asymptomatic heterozygous FH patients (48% men; 46 ± 15 years) on long-term (10.0 ± 7.8 years) statin treatment and 103 controls (32% men, 47 ± 16 years)., Results: The frequency of carotid plaques and C-IMT did not differ significantly between the FH patients and controls (69 (31%) versus 24 (23%), p = 0.1 and 0.58 ± 0.13 versus 0.58 ± 0.12 mm, p = 0.9, respectively). In a subgroup of 49 FH patients who underwent cardiac computed tomography, coronary artery calcification correlated with carotid plaque presence (R = 0.47; p = 0.001), but not with C-IMT (R = 0.20; p = 0.2)., Conclusions: Carotid plaques and C-IMT did not differ between long-term statin-treated heterozygous FH patients and healthy controls. This shows that long-term statin treatment in these FH patients reduces carotid atherosclerosis to a degree of a healthy population. These findings strongly suggests that sonography of the carotid arteries during follow-up of statin-treated FH patients has limited value., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The aim of this study is to assess the long-term effects of alcohol dosage in alcohol septal ablation (ASA) on mortality and adverse arrhythmic events (AAE)., Background: ASA can be performed to reduce left ventricular outflow tract (LVOT) obstruction in patients with hypertrophic cardiomyopathy (HCM). However, the effect of alcohol dosage on long-term outcomes is unknown., Methods: This retrospective cohort study includes 296 HCM patients (age 60 ± 22 years, 58% male) who underwent ASA because of symptomatic LVOT obstruction. Twenty-nine patients (9.8%) were excluded because the alcohol dosage could not be retrieved. Primary endpoints were all-cause mortality and AAE., Results: During 6.3 ± 3.7 years of follow-up, all-cause mortality and AAE rates were similar in patients who received ≤2.0 mL (n = 142) and >2.0 mL (n = 121) alcohol during ASA. Age was the only independent predictor of mortality (HR 1.1 95% CI 1.0-1.1, P < 0.001). Predictors of AAE were maximum CK-MB >240 U/L (HR 3.3 95% CI 1.5-7.2, P = 0.003), and sudden cardiac death survivor (HR 5.9 95% CI 1.7-20.3, P = 0.004). There was a mild to moderate correlation between CK-MB levels and amount of alcohol (Spearman's ρ 0.39, P < 0.001), cross-sectional area of the target septal branch ostium/ostia (Spearman's ρ 0.19, P = 0.003), and maximum ventricular wall thickness (Spearman's ρ 0.17, P = 0.006)., Conclusions: Alcohol dosage appears not to have a long-term effect on mortality and AAE. A larger infarct size created by ASA increases the risk of AAE, and extended monitoring of these patients is advised. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The role of early coronary revascularization in the management of stable coronary artery disease remains controversial. The aim of this study was to evaluate the impact of early coronary revascularization on long-term outcomes (>10 years) after an ischemic dobutamine stress echocardiography (DSE) in patients with known or suspected coronary artery disease. Patients without stress-induced ischemia on DSE and those who underwent late coronary revascularization (>90 days after DSE) were excluded. The final study cohort consisted of 905 patients. A DSE with a peak wall motion score index of 1.1 to 1.7 was considered mild to moderately abnormal (n = 460), and >1.7 was markedly abnormal (n = 445). End points were all-cause and cardiac mortality. The impact of early coronary revascularization on outcomes was assessed using Kaplan-Meier survival analysis and Cox's proportional hazard regression models. Early coronary revascularization was performed in 222 patients (percutaneous coronary intervention in 113 [51%] and coronary artery bypass grafting in 109 patients [49%]). During a median follow-up time of 10 years (range 8 to 15), 474 deaths (52%) occurred, of which were 241 (51%) due to cardiac causes. Kaplan-Meier survival curves showed that both in patients with a markedly abnormal DSE and a mild-to-moderately abnormal DSE, early revascularization was associated with better long-term outcomes. Multivariable analyses revealed that early revascularization had a beneficial effect on all-cause mortality (hazard ratio 0.60, 95% confidence interval 0.46 to 0.79) and cardiac mortality (hazard ratio 0.49, 95% confidence interval 0.34 to 0.72). In conclusion, early coronary revascularization has a beneficial impact on long-term outcomes in patients with myocardial ischemia on DSE. Early coronary revascularization was associated with better outcomes not only in patients with a markedly abnormal DSE but also in those with a mild to moderately abnormal DSE., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Many studies have examined the prognostic value of myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) for the prediction of short- to medium-term outcomes. However, the long-term prognostic value of MPI in patients with diabetes mellitus remains unclear. Therefore, this study assessed the long-term prognostic value of MPI in a high-risk cohort of patients with diabetes mellitus., Methods and Results: A high-risk cohort of 207 patients with diabetes mellitus who were unable to undergo exercise testing underwent dobutamine stress MPI. Follow-up was successful in 206 patients; 12 patients were excluded due to early revascularization. The current data are based on the remaining 194 patients. Follow-up end points were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction. The Kaplan-Meier survival curves were constructed, and univariable and multivariable analyses were performed to identify predictors of long-term outcome. During a mean follow-up of 8.1 ± 5.9 years, 134 (69%) patients died of which 68 (35%) died due to cardiac causes. Nonfatal myocardial infarction occurred in 24 patients (12%), and late (>60 days) coronary revascularization was performed in 61 (13%) patients. Survival analysis showed that MPI provided optimal risk stratification up to 4 years after testing. After that period, the outcome was comparable in patients with normal and abnormal MPI. Multivariable analyses showed that MPI provided incremental prognostic value up to 4 years after testing., Conclusion: In high-risk patients with diabetes mellitus, dobutamine MPI provides incremental prognostic information in addition to clinical data for a 4-year period after testing., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

The prognostic value of dobutamine stress echocardiography (DSE) at >10-year follow-up is unknown. The aim of this study was to assess the very long-term prognostic value of DSE in a high-risk cohort of patients with known or suspected coronary artery disease. This prospective, single-center study included 3,381 patients who underwent DSE from January 1990 to January 2003. Two-dimensional echocardiographic images were acquired at rest, during dobutamine stress, and during recovery. Follow-up events were collected and included overall mortality, cardiac death, nonfatal myocardial infarction, and revascularization. The incremental value of DSE in the prediction of selected end points was evaluated using multivariate Cox proportional hazard analysis. During a mean follow-up of 13 ± 3.2 years (range 7.3 to 20.5 years), there were 1,725 deaths (51%), of which 1,128 (33%) were attributed to cardiac causes. Patients with an abnormal DSE had a higher mortality rate (44% vs 35% at 15-year follow-up, p <0.001) than those with a normal DSE. When comparing echocardiographic variables at rest to variables at maximum dose dobutamine, the chi-square of the test improved from 842 to 870 (p <0.0001) and from 684 to 740 (p <0.0001) for all-cause mortality and cardiac death, respectively. DSE provided incremental value in predicting all-cause mortality, cardiac death, and hard cardiac events. There seems, however, to be a "warranty period" of approximately 7 years, when the survival curves of a normal and abnormal DSE no longer diverge., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to compare outcomes of alcohol septal ablation (ASA) in young and elderly patients with obstructive hypertrophic cardiomyopathy (HCM)., Background: The American College of Cardiology Foundation/American Heart Association guidelines reserve ASA for elderly patients and patients with serious comorbidities. Information on long-term age-specific outcomes after ASA is scarce., Methods: This cohort study included 217 HCM patients (age 54 ± 12 years) who underwent ASA because of symptomatic left ventricular outflow tract obstruction. Patients were divided into young (age ≤55 years) and elderly (age >55 years) groups and matched by age in a 1:1 fashion to nonobstructive HCM patients., Results: Atrioventricular block following ASA was more common in elderly patients (43% vs. 21%; p = 0.001), resulting in pacemaker implantation in 13% and 5%, respectively (p = 0.06). Residual left ventricular outflow tract gradient, post-procedural New York Heart Association functional class, and necessity for additional septal reduction therapy was comparable between age groups. During a follow-up of 7.6 ± 4.6 years, 54 patients died. The 5- and 10-year survival following ASA was 95% and 90% in patients age ≤55 years and 93% and 82% in patients age >55 years, which was comparable to their control groups. The annual adverse arrhythmic event rate following ASA was 0.7%/year in young patients and 1.4%/year in elderly patients, which was comparable to their control groups., Conclusions: ASA is similarly effective for reduction of symptoms in young and elderly patients; however, younger patients have a lower risk of procedure-related atrioventricular conduction disturbances. The long-term mortality rate and risk of adverse arrhythmic events following ASA are low, both in young and elderly patients, and are comparable to age-matched nonobstructive HCM patients., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Contrast-enhanced ultrasound (CEUS) is increasingly being used to evaluate patients with known or suspected atherosclerosis. The administration of a microbubble contrast agent in conjunction with ultrasound results in an improved image quality and provides information that cannot be assessed with standard B-mode ultrasound. CEUS is a high-resolution, noninvasive imaging modality, which is safe and may benefit patients with coronary, carotid, or aortic atherosclerosis. CEUS allows a reliable assessment of endocardial borders, left ventricular function, intracardiac thrombus and myocardial perfusion. CEUS results in an improved detection of carotid atherosclerosis, and allows assessment of high-risk plaque characteristics including intraplaque vascularization, and ulceration. CEUS provides real-time bedside information in patients with a suspected or known abdominal aortic aneurysm or aortic dissection. The absence of ionizing radiation and safety of the contrast agent allow repetitive imaging which is particularly useful in the follow-up of patients after endovascular aneurysm repair. New developments in CEUS-based molecular imaging will improve the understanding of the pathophysiology of atherosclerosis and may in the future allow to image and directly treat cardiovascular diseases (theragnostic CEUS). Familiarity with the strengths and limitations of CEUS may have a major impact on the management of patients with atherosclerosis.

Background: Coronary microvascular dysfunction (CMD) is an important feature of hypertrophic cardiomyopathy (HCM), which contributes negatively to symptoms and long-term outcome. Previous in vivo imaging studies in HCM suggest that left ventricular outflow tract (LVOT) gradient and genetic status are important contributors to CMD. CMD may be caused by reduced capillary density. Here, we investigated whether a reduction in capillary density is related to genetic status or LVOT gradient severity in an in vitro study of HCM cardiac samples., Methods: Using immunofluorescence microscopy, we analysed capillaries (Cap) and cardiomyocytes (CM) in myectomy specimens from 18 HCM patients with maximum left ventricular (LV) wall thickness ≥15 mm. All subjects exhibited significant LVOT obstruction, necessitating septal myectomy. In addition, control myocardium from the LV septal wall was collected at autopsy of 6 individuals that suffered a noncardiac death., Results: CM area was higher in patients with HCM compared to controls. Capillary density was significantly lower in patients with HCM compared with controls (1425 ± 262 vs. 2543 ± 509 Cap/mm(2) , P < 0·001), as was the number of Cap per CM corrected for CM area (2·2 ± 0·5 vs. 4·2 ± 0·9 Cap/CM area, P < 0·001). Capillary density did not differ between genotype-negative and genotype-positive HCM patients at similar resting LVOT gradients. A significant correlation was present between resting LVOT gradient and CM area (r = 0·73, P < 0·001), capillary density (r = -0·74, P < 0·001) and the number of Cap per CM corrected for CM area (r = -0·82, P < 0·001)., Conclusions: Our data indicate that LVOT gradient, rather than genetic status, is associated with reduced capillary density in HCM., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand binding repeat (LR11) and its soluble form (sLR11) play a role in the progression of atherosclerosis. We investigated the involvement of LR11 and sLR11 in CVD development in FH patients and in LDLR deficient (Ldlr(-/-)) mice., Approach and Results: In statin-treated asymptomatic male heterozygous FH subjects, plasma sLR11 levels correlated with carotid intima-media thickness. Increased plasma sLR11 levels were found in Ldlr(-/-) and also in wild-type mice exclusively after high-fat feeding. Hepatic LR11 mRNA levels, however, were higher in chow-fed Ldlr(-/-) in comparison with wild-type mice and were further increased after a high fat diet. Similar results were obtained with Apoe(-/-) mice, but not with wild-type mice. LR11 mRNA and protein levels and release of sLR11 from cultured HepG2 and aortic smooth muscle cells were upregulated by postprandial triglyceride-rich lipoproteins (TGRL). Overexpression of human LR11 in CHO cells resulted in increased binding and association of 12I-labeled TGRL, but not of 12I-labeled LDL., Conclusion: Our data strongly suggest an involvement of LR11 in mediating the harmful effects of a high-fat diet on CVD progression. Elevated sLR11 levels may increase the CVD risk especially in subjects with delayed clearance of triglyceride-rich remnants, such as in FH patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

QRS duration is of prognostic relevance in patients with several underlying heart diseases. Short-term data also show the prognostic value of QRS duration in lower risk groups of patients. The aim of this study was to investigate the long-term prognostic value of QRS duration in patients with known or suspected coronary artery disease. The study cohort consisted of 512 patients (308 men, mean age 60 ± 11 years) who underwent myocardial perfusion imaging (MPI) for the evaluation of suspected or known coronary artery disease. Follow-up data were collected to assess the prognostic value of QRS duration, alongside clinical characteristics and MPI results. End points were cardiac death and cardiac death or nonfatal myocardial infarction (MI). During a mean follow-up of 8.6 ± 5.2 years, 290 patients (60%) died, with 139 deaths (27%) attributable to cardiac causes. Nonfatal MI occurred in 28 patients (6%), and 127 patients (25%) underwent late coronary revascularization (>3 months). Patients with QRS duration <120 ms had annualized cardiac death rates and cardiac death or nonfatal MI rates of 2.2% and 2.3%, respectively, compared with those of 4.1% and 4.4% in patients with QRS duration ≥120 ms. Multivariate models identified QRS duration ≥120 ms as an independent predictor of both end points, on top of clinical characteristics and MPI results. In conclusion, QRS duration ≥120 ms is an independent predictor of cardiac death and cardiac death or nonfatal MI, after adjustment for clinical characteristics and MPI results., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The aim of this meta-analysis was to compare long-term outcomes after myectomy and alcohol septal ablation (ASA) in patients with hypertrophic cardiomyopathy (HCM)., Background: Surgical myectomy and ASA are both accepted treatment options for medical therapy-resistant obstructive HCM. Previous meta-analyses only evaluated short-term outcomes., Methods: A systematic review was conducted for eligible studies with a follow-up of at least 3 years. Primary outcomes were all-cause mortality and (aborted) sudden cardiac death (SCD). Secondary outcomes were periprocedural complications, left ventricular outflow tract gradient, and New York Heart Association functional class after ≥3 months, and reintervention. Pooled estimates were calculated using a random-effects meta-analysis., Results: Sixteen myectomy cohorts (n = 2,791; mean follow-up, 7.4 years) and 11 ASA cohorts (n = 2,013; mean follow-up, 6.2 years) were included. Long-term mortality was found to be similarly low after ASA (1.5% per year) compared with myectomy (1.4% per year, p = 0.78). The rate of (aborted) SCD, including appropriate implantable cardioverter defibrillator shocks, was 0.4% per year after ASA and 0.5% per year after myectomy (p = 0.47). Permanent pacemaker implantation was performed after ASA in 10% of the patients compared with 4.4% after myectomy (p < 0.001). Reintervention was performed in 7.7% of the patients who underwent ASA compared with 1.6% after myectomy (p = 0.001)., Conclusions: Long-term mortality and (aborted) SCD rates after ASA and myectomy are similarly low. Patients who undergo ASA have more than twice the risk of permanent pacemaker implantation and a 5 times higher risk of the need for additional septal reduction therapy compared with those who undergo myectomy., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Despite multiple studies on the diagnostic and prognostic use of dobutamine myocardial perfusion imaging (MPI), information on its long-term prognostic value is scarce. The aim of this study was to assess the value of this technique for the prediction of very long-term outcome., Methods: A total of 721 patients with limited exercise capacity underwent dobutamine MPI for the evaluation of suspected or known coronary artery disease. 719 of 721 patients attended follow-up (99.7%). Twenty-eight patients who underwent early coronary revascularization were excluded from analysis. Endpoints were all-cause mortality, cardiac death, nonfatal infarction, and coronary revascularization. Kaplan-Meier survival curves were constructed, and univariate and multivariate analyses were performed to identify predictors of long-term outcome., Results: The mean age of patients was 60 ± 11 years, and 61% were male. Myocardial perfusion abnormalities were present in 381 patients (55%) and included fixed defects in 190 patients (27%) and reversible defects in 191 patients (28%). During a median follow-up time of 14 years (range 0-16), 295 deaths occurred (43%), of which 158 were cardiac deaths (23%). Nonfatal myocardial infarction occurred in 35 (5%), and late coronary revascularization was performed on 133 patients (19%). An abnormal dobutamine MPI provided significant prognostic information for prediction of cardiac death, hard cardiac events, and MACE, after adjustment for significant clinical variables and stress test variables., Conclusions: Dobutamine MPI provides incremental prognostic information for the prediction of cardiovascular outcomes in patients with limited exercise capacity. The long-term prognosis of patients with limited exercise capacity who have an abnormal dobutamine MPI is significantly worse than those with a normal MPI.

Background: The recently released 2014 European Society of Cardiology guidelines of hypertrophic cardiomyopathy (HCM) use a new clinical risk prediction model for sudden cardiac death (SCD), based on the HCM Risk-SCD study. Our study is the first external and independent validation of this new risk prediction model., Methods and Results: The study population consisted of a consecutive cohort of 706 patients with HCM without prior SCD event, from 2 tertiary referral centers. The primary end point was a composite of SCD and appropriate implantable cardioverter-defibrillator therapy, identical to the HCM Risk-SCD end point. The 5-year SCD risk was calculated using the HCM Risk-SCD formula. Receiver operating characteristic curves and C-statistics were calculated for the 2014 European Society of Cardiology guidelines, and risk stratification methods of the 2003 American College of Cardiology/European Society of Cardiology guidelines and 2011 American College of Cardiology Foundation/American Heart Association guidelines. During follow-up of 7.7±5.3 years, SCD occurred in 42 (5.9%) of 706 patients (ages 49±16 years; 34% women). The C-statistic of the new model was 0.69 (95% CI, 0.57-0.82; P=0.008), which performed significantly better than the conventional risk factor models based on the 2003 guidelines (C-statistic of 0.55: 95% CI, 0.47-0.63; P=0.3), and 2011 guidelines (C-statistic of 0.60: 95% CI, 0.50-0.70; P=0.07)., Conclusions: The HCM Risk-SCD model improves the risk stratification of patients with HCM for primary prevention of SCD, and calculating an individual risk estimate contributes to the clinical decision-making process. Improved risk stratification is important for the decision making before implantable cardioverter-defibrillator implantation for the primary prevention of SCD., (© 2015 American Heart Association, Inc.)

In standard B-mode ultrasound (BMUS), segmentation of the lumen of atherosclerotic carotid arteries and studying the lumen geometry over time are difficult owing to irregular lumen shapes, noise, artifacts, and echolucent plaques. Contrast enhanced ultrasound (CEUS) improves lumen visualization, but lumen segmentation remains challenging owing to varying intensities, CEUS-specific artifacts and lack of tissue visualization. To overcome these challenges, we propose a novel method using simultaneously acquired BMUS&CEUS image sequences. Initially, the method estimates nonrigid motion (NME) from the image sequences, using intensity-based image registration. The motion-compensated image sequence is then averaged to obtain a single "epitome" image with improved signal-to-noise ratio. The lumen is segmented from the epitome image through an intensity joint-histogram classification and a graph-based segmentation. NME was validated by comparing displacements with manual annotations in 11 carotids. The average root mean square error (RMSE) was 112±73 μm . Segmentation results were validated against manual delineations in the epitome images of two different datasets, respectively containing 11 (RMSE 191±43 μm) and 10 (RMSE 351±176 μm ) carotids. From the deformation fields, we derived arterial distensibility with values comparable to the literature. The average errors in all experiments were in the inter-observer variability range. To the best of our knowledge, this is the first study exploiting combined BMUS&CEUS images for atherosclerotic carotid lumen segmentation.

Purpose: Intraplaque neovascularization (IPN) is an increasingly studied marker of the vulnerable atherosclerotic plaque, and contrast-enhanced ultrasound (CEUS) is an in vivo imaging technique for the assessment of IPN. The purpose of this study was to test novel quantification methods for the detection of carotid IPN using CEUS., Materials and Methods: 25 patients with established carotid atherosclerosis underwent bilateral carotid CEUS using a Philips iU-22 ultrasound system with an L9 - 3 transducer. Visual scoring of IPN was performed using a 3-point score. Quantification of IPN was performed using novel custom developed software. In short, regions of interest were drawn over the atherosclerotic plaques. After motion compensation, several IPN features were calculated. Statistical analysis was performed using Spearman's rho. Reproducibility of the quantification features was calculated using intra-class correlation coefficients and mean differences between calculations., Results: 45 carotid arteries were available for the quantification of IPN. The quantification of IPN was feasible in all 45 carotid plaques. The IPN area, IPN area ratio and neovessel count had a good correlation with the visual IPN score (respectively ρ = 0.719, ρ = 0.538, ρ = 0.474 all p < 0.01). The intra-observer and inter-observer agreement was good to excellent (p < 0.01). The intra-observer and inter-observer variability was low., Conclusion: The quantification of carotid IPN on CEUS is feasible and provides multiple features on carotid IPN. Accurate quantitative assessment of IPN may be important to recognize and to monitor changes during therapy in vulnerable atherosclerotic plaques., (© Georg Thieme Verlag KG Stuttgart · New York.)

Myocardial perfusion single-photon emission computed tomography is a routine technique for the evaluation of coronary artery disease. However, information on the very long term prognostic value of dobutamine stress single-photon emission computed tomographic myocardial perfusion imaging (MPI) in patients with limited exercise capacity is scarce. The aim of this study was to assess the long-term prognostic value of dobutamine stress technetium-99m ((99m)Tc)-sestamibi MPI in these patients. The study population consisted of a high-risk cohort of 531 consecutive patients with limited exercise capacity who underwent dobutamine stress (99m)Tc-sestamibi MPI for the assessment of known or suspected coronary artery disease. Follow-up was successful in 528 patients. Because of early revascularization, 55 patients were excluded. The present data are based on 473 patients. The end points were all-cause mortality, cardiac death, nonfatal myocardial infarction, and late (>60 days) coronary revascularization. Kaplan-Meier survival curves were performed and univariate and multivariate analyses were performed to identify predictors of very long term outcome. The mean age of the patients was 61 ± 12 years, and 58% were men. Abnormal results (defined as the presence of reversible or fixed defects) were observed in 312 patients (66%). During a mean follow-up period of 11.3 ± 6.7 years, 287 patients (61%) died (all-cause mortality), of whom 125 (26%) died due to cardiac causes. Nonfatal myocardial infarction occurred in 59 patients (12%). Late coronary revascularization was performed in 61 patients (13%). Univariate predictors of major cardiac events included age, male gender, previous infarction, diabetes mellitus, history of angina, heart failure, ST-segment changes, abnormal results on (99m)Tc-sestamibi scan, reversible defect, fixed defect, summed rest score, and summed stress score. Multivariate analysis identified abnormal results on MPI as a strong independent predictor of major adverse cardiac events. In conclusion, in patients with limited exercise capacity, dobutamine stress (99m)Tc-sestamibi single-photon emission computed tomography provides incremental prognostic information in addition to clinical and stress test parameters for the prediction of very long term outcomes., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17,000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10(-4)). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an 'extreme genetics' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.

Severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HC) may benefit from surgical myectomy. In patients with enlarged mitral leaflets and mitral regurgitation, myectomy can be combined with anterior mitral leaflet extension (AMLE) to stiffen the midsegment of the leaflet. The aim of this study was to evaluate the long-term results of myectomy combined with AMLE in patients with obstructive HC. This prospective, observational, single-center cohort study included 98 patients (49 ± 14 years, 37% female) who underwent myectomy combined with AMLE from 1991 to 2012. End points included all-cause mortality and change in clinical and echocardiographic characteristics. Mortality was compared with age- and gender-matched patients with nonobstructive HC and subjects from the general population. Long-term follow-up was 8.3 ± 6.1 years. There was no operative mortality, and New York Heart Association class was reduced from 2.8 ± 0.5 to 1.3 ± 0.5 (p <0.001), left ventricular outflow tract gradient from 93 ± 25 to 9 ± 8 mm Hg (p <0.001), mitral valve regurgitation from grade 2.0 ± 0.9 to 0.5 ± 0.8 (p <0.001), and systolic anterior motion of the mitral valve from grade 2.4 ± 0.9 to 0.1 ± 0.3 (p <0.001). The 1-, 5-, 10-, and 15-year cumulative survival rates were 98%, 92%, 86%, and 83%, respectively, and did not differ from the general population (99%, 97%, 92%, and 85%, respectively, p = 0.3) or patients with nonobstructive HC (98%, 97%, 88%, and 83%, respectively, p = 0.8). In conclusion, in selected patients with obstructive HC, myectomy combined with AMLE is a low-risk surgical procedure. It results in long-term symptom relief and survival similar to the general population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Carotid plaque segmentation in B-mode ultrasound (BMUS) and contrast-enhanced ultrasound (CEUS) is crucial to the assessment of plaque morphology and composition, which are linked to plaque vulnerability. Segmentation in BMUS is challenging because of noise, artifacts and echo-lucent plaques. CEUS allows better delineation of the lumen but contains artifacts and lacks tissue information. We describe a method that exploits the combined information from simultaneously acquired BMUS and CEUS images. Our method consists of non-rigid motion estimation, vessel detection, lumen-intima segmentation and media-adventitia segmentation. The evaluation was performed in training (n = 20 carotids) and test (n = 28) data sets by comparison with manually obtained ground truth. The average root-mean-square errors in the training and test data sets were comparable for media-adventitia (411 ± 224 and 393 ± 239 μm) and for lumen-intima (362 ± 192 and 388 ± 200 μm), and were comparable to inter-observer variability. To the best of our knowledge, this is the first method to perform fully automatic carotid plaque segmentation using combined BMUS and CEUS., (Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Intraplaque neovascularization (IPN) is an important biomarker of atherosclerotic plaque vulnerability. As IPN can be detected by contrast enhanced ultrasound (CEUS), imaging-biomarkers derived from CEUS may allow early prediction of plaque vulnerability. To select the best quantitative imaging-biomarkers for prediction of plaque vulnerability, a systematic analysis of IPN with existing and new analysis algorithms is necessary. Currently available commercial contrast quantification tools are not applicable for quantitative analysis of carotid IPN due to substantial motion of the carotid artery, artifacts, and intermittent perfusion of plaques. We therefore developed a specialized software package called Carotid intraplaque neovascularization quantification software (CINQS). It was designed for effective and systematic comparison of sets of quantitative imaging biomarkers. CINQS includes several analysis algorithms for carotid IPN quantification and overcomes the limitations of current contrast quantification tools and existing carotid IPN quantification approaches. CINQS has a modular design which allows integrating new analysis tools. Wizard-like analysis tools and its graphical-user-interface facilitate its usage. In this paper, we describe the concept, analysis tools, and performance of CINQS and present analysis results of 45 plaques of 23 patients. The results in 45 plaques showed excellent agreement with visual IPN scores for two quantitative imaging-biomarkers (The area under the receiver operating characteristic curve was 0.92 and 0.93).

Objectives: The aim of this study was to determine the long-term outcomes (all-cause mortality and sudden cardiac death [SCD]) after medical therapy, alcohol septal ablation (ASA), and myectomy in patients with hypertrophic cardiomyopathy (HCM)., Background: Therapy-resistant obstructive HCM can be treated both surgically and percutaneously. But there is no consensus on the long-term effects of ASA, especially on SCD., Methods: This study included 1,047 consecutive patients with HCM (mean age 52 ± 16 years, 61% men) from 3 tertiary referral centers. A total of 690 patients (66%) had left ventricular outflow tract gradients ≥ 30 mm Hg, of whom 124 (12%) were treated medically, 316 (30%) underwent ASA, and 250 (24%) underwent myectomy. Primary endpoints were all-cause mortality and SCD. Kaplan-Meier graphs and Cox regression models were used for statistical analyses., Results: The mean follow-up period was 7.6 ± 5.3 years. Ten-year survival was similar in medically treated patients (84%), ASA patients (82%), myectomy patients (85%), and patients with nonobstructive HCM (85%) (log-rank p = 0.50). The annual rate of SCD was low after invasive therapy: 1.0%/year in the ASA group and 0.8%/year in the myectomy group. Multivariate analysis demonstrated that the risk for SCD was lower after myectomy compared with the ASA group (hazard ratio: 2.1; 95% confidence interval: 1.0 to 4.4; p = 0.04) and the medical group (hazard ratio: 2.3; 95% confidence interval: 1.0 to 5.2; p = 0.04)., Conclusions: Patients with obstructive HCM who are treated at referral centers for HCM care have good survival and low SCD risk, similar to that of patients with nonobstructive HCM. The SCD risk of patients after myectomy was lower than after ASA or in the medical group., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Patients with diabetes mellitus (DM) are at severely increased risk of developing atherosclerosis. Intraplaque neovascularization (IPN) and plaque ulceration are markers of the vulnerable plaque, which is at an increased risk of rupture and may lead to cardiovascular events. The aim of this study was to assess the prevalence of subclinical carotid atherosclerosis, intraplaque neovascularization (IPN), and plaque ulceration in asymptomatic patients with DM., Methods and Results: A total of 51 asymptomatic patients with DM underwent standard carotid ultrasound in conjunction with contrast-enhanced ultrasound (CEUS) to assess the prevalence of subclinical atherosclerosis, IPN, and plaque ulceration. Subclinical atherosclerosis was defined as the presence of atherosclerotic plaque, according to the Mannheim consensus. Semi-automated quantification software was used to assess IPN in suitable plaques. Plaque ulceration was defined as a disruption of the plaque-lumen border of ≥ 1 × 1 mm. A total of 408 carotid segments in 102 carotid arteries were investigated. Forty-six (90%) patients had subclinical atherosclerotic plaques, with a median plaque thickness of 2.4 mm (inter-quartile range 1.9-3.0). CEUS revealed IPN in 88% of the patients. In 10 carotid segments (8%), the plaque had an ulcerated surface. The presence of IPN could not be predicted by the presence of clinical characteristics including complications of DM (P > 0.05)., Conclusion: Patients with DM have a high prevalence (90%) of subclinical carotid atherosclerosis. Severe IPN and plaque ulceration, which are markers of the vulnerable plaque type, were detected in, respectively, 13 and 9% of these patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)