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Background: The early diastolic paradoxical midventricular flow is suggestive of apical aneurysm (AA) formation in hypertrophic cardiomyopathy (HCM). We aimed to determine whether early diastolic paradoxical midventricular flow may be a useful screening tool in patients, following the time progression of HCM to the aneurysmal stage. Methods: One hundred twenty-one HCM patients with dominant hypertrophy in the mid and apical segments, based on echocardiography and/or cardiovascular magnetic resonance, were selected from our HCM database, which comprises 1,332 patients. They were further stratified according to the presence of AA. All imaging studies in a period of 16 years (2005-2021) were considered for time progression. Midventricular Doppler (pulsed-wave, continuous-wave, color, and color M mode) were analyzed. Results: Thirty-five patients (29% of the study group and 2.6% of all HCM patients) had AA. Early diastolic paradoxical midventricular flow had a sensitivity of 92% and specificity of 98.6% for the detection of AA in the study group. In 108 patients, follow-up echocardiography was performed (median, 5 [3-9] studies). Sixteen patients (15%) with 10 [7-12] years of follow-up displayed progressive time changes in left ventricle (LV) apical morphology and/or mid-LV flow. Ten patients (9%) progressed to an AA, during 7 [4-11] years of follow-up. Patients progressing to AA were younger (P = .009), with more severe LV hypertrophy (P = .01) and more often a significant mid-LV systolic gradient (≥30 mm Hg, P < .001). A wall thickness over 20 mm had 70% sensitivity and 69% specificity in detecting evolution toward AA. With significant systolic gradient, sensitivity was 80% and specificity was 62%. Furthermore, patients with AA had a higher incidence of ventricular tachycardia (log-rank P = .03). Conclusions: Early diastolic paradoxical midventricular flow reliably detects AA presence and should prompt extra imaging studies. In HCM with mid and apical dominant involvement there is a progressive trend toward aneurysm formation, especially in patients with wall thickness over 20 mm and significant mid-LV systolic gradient (≥30 mm Hg), which can be monitored through serial Doppler studies.

Aims: The aim of the present study was to compare the rate of actionable arrhythmic events between patients with hypertrophic cardiomyopathy (HCM) who are monitored with an insertable cardiac monitor (ICM) or Holter monitoring. Methods: We studied 50 patients (mean age 52 years, 72% men) with HCM at low or intermediate risk for sudden cardiac death (SCD), of whom 25 patients received an ICM between November 2014 and February 2019. We retrospectively identified a control group of 25 patients who were matched on age, sex, and HCM Risk-SCD score category. The mean HCM Risk-SCD score was 3.41 ± 1.31 and 3.31 ± 1.43 for the ICM and Holter groups, respectively. The primary endpoint was an actionable event which was defined as an arrhythmic event resulting in a change in patient management. The secondary endpoint was the occurrence of ventricular tachycardia (VT). Results: The cumulative actionable event rate at 30 months was higher in the ICM group (51 vs. 27%, log-rank p value n = 3). Overall, 4 implantable cardioverter-defibrillators were implanted for primary prevention (n = 2 in each group). The cumulative rate of VT episodes at 30 months was similar between groups (23% [ICM group] vs. 42% [Holter group], log-rank p value = 0.71). Furthermore, the characteristics of VT were similar between groups with regard to the number of beats and rate. Conclusions: In adults with HCM, an ICM will detect more arrhythmic events requiring an intervention than a conventional Holter strategy. In contrast, the diagnostic yield of detecting VT seems similar for both groups.

Contrast-enhanced ultrasound (CEUS) is increasingly being used to identify patients with carotid plaques that are vulnerable to rupture, so-called vulnerable atherosclerotic plaques, by assessment of intraplaque neovascularization. A complete overview of the strengths and limitations of carotid CEUS is currently not available. The aim of this systematic review was to provide a complete overview of existing publications on the role of CEUS in assessment of carotid intraplaque neovascularization. The systematic review of the literature yielded 52 studies including a total of 4660 patients (mean age: 66 y, 71% male) who underwent CEUS for the assessment of intraplaque neovascularization. The majority of the patients (76%) were asymptomatic and had no history of transient ischemic attack (TIA) or stroke. The assessment of intraplaque neovascularization was mostly performed using a visual scoring system; several studies used time-intensity curves or dedicated quantification software to optimize analysis. In 17 studies CEUS was performed in patients before carotid surgery (endarterectomy), allowing a comparison of pre-operative CEUS findings with histologic analysis of the tissue sample that is removed from the carotid artery. In a total of 576 patients, the CEUS findings were compared with histopathological analysis of the plaque after surgery. In 16 of the 17 studies, contrast enhancement was found to correlate with the presence and degree of intraplaque neovascularization on histology. Plaques with a larger amount of contrast enhancement had significantly increased density of microvessels in the corresponding region on histology. In conclusion, CEUS is a readily available imaging modality for the assessment of patients with carotid atherosclerosis, providing information on atherosclerotic plaques, such as ulceration and intraplaque neovascularization, which may be clinically relevant. The ultimate clinical goal is the early identification of carotid atherosclerosis to start early preventive therapy and prevent clinical complications such as TIA and stroke.

Purpose Poor left ventricular (LV) function may affect the physiological intraventricular blood flow and physiological vortex formation. The aim of this study was to investigate the pattern of intraventricular blood flow dynamics in patients with LV assist devices (LVADs) using echocardiographic particle image velocimetry. Materials and methods This prospective study included 17 patients (mean age 57 ± 11 years, 82% male) who had received an LVAD (HeartMate 3, Abbott Laboratories, Chicago, Illinois, USA) because of end-stage heart failure and poor LV function. Eleven (64%) patients had ischemic cardiomyopathy, and six patients (36%) had nonischemic cardiomyopathy. All patients underwent echocardiography, including intravenous administration of an ultrasound-enhancing agent (SonoVue, Bracco, Milan, Italy). Echocardiographic particle image velocimetry was used to quantify LV blood flow dynamics, including vortex formation (Hyperflow software, Tomtec imaging systems Gmbh, Unterschleissheim, Germany). Results Contrast-enhanced ultrasound was well tolerated in all patients and was performed without adverse reactions or side effects. The LVAD function parameters did not change during or after the ultrasound examination. The LVAD flow was on average 4.3 ± 0.3 L/min, and the speed was 5247 ± 109 rotations/min. The quantification of LV intraventricular flow demonstrated substantial impairment of vortex parameters. The energy dissipation, vorticity, and kinetic energy fluctuation indices were severely impaired. Conclusions Echo particle velocimetry is safe and feasible for the quantitative assessment of intraventricular flow in patients with an LVAD. The intraventricular LV flow and vortex parameters are severely impaired in these patients.

We apply a high frame rate (over 500 Hz) tissue Doppler method to measure the propagation velocity of naturally occurring shear waves (SW) generated by aortic and mitral valves closure. The aim of this work is to demonstrate clinical relevance. We included 45 healthy volunteers and 43 patients with hypertrophic cardiomyopathy (HCM). The mitral SW (4.68 ± 0.66 m/s) was consistently faster than the aortic (3.51 ± 0.38 m/s) in all volunteers (p < 0.0001). In HCM patients, SW velocity correlated with E/e’ ratio (r = 0.346, p = 0.04 for aortic SW and r = 0.667, p = 0.04 for mitral SW). A subgroup of 20 volunteers were matched for age and gender to 20 HCM patients. In HCM, the mean velocity of 5.1 ± 0.7 m/s for the aortic SW (3.61 ± 0.46 m/s in matched volunteers, p < 0.0001) and 6.88 ± 1.12 m/s for the mitral SW(4.65 ± 0.77 m/s in matched volunteers, p < 0.0001). A threshold of 4 m/s for the aortic SW correctly classified pathologic myocardium with a sensitivity of 95% and specificity of 90%. Naturally occurring SW can be used to assess differences between normal and pathologic myocardium.

BACKGROUND There is overlap in genetic causes and cardiac features in noncompaction cardiomyopathy (NCCM), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM).OBJECTIVES The goal of this study was to predict phenotype and outcome in relatives according to the clinical features and genotype of NCCM index cases.METHODS Retrospective DNA and cardiac screening of relatives of 113 families from 143 index patients were used to classify NCCM cases according to the cardiac phenotype. These cases were classified as isolated NCCM, NCCM with left ventricular (LV) dilation (DCM), and NCCM with LV hypertrophy (HCM).RESULTS In 58 (51%) families, screening identified 73 relatives with NCCM and 34 with DCM or HCM without NCCM. The yield of family screening was higher in families with a mutation (p CONCLUSIONS The phenotype of relatives may be predicted according to the NCCM phenotype and the mutation of index patients. NCCM phenotypes were related to outcome. In this way, clinical and genetic features of index patients may help prediction of outcome in relatives. (C) 2019 by the American College of Cardiology Foundation.

Background Currently, the eligibility for a subcutaneous implantable defibrillator (S-ICD) system relies on a pre-implant vector screening based on the automated screening tool (AST). We investigated which 12-lead ECG characteristics are associated with eligibility for an S-ICD in a heterogeneous population at risk for sudden cardiac death (SCD). The goal is to determine patient eligibility for S-ICD using the standard 12-lead ECG, thereby avoiding additional AST screening. Methods We evaluated the eligibility for an S-ICD in 254 consecutive patients at risk for SCD. We identified 12-lead ECG parameters which were independently associated with AST passing (≥1 vector) using multivariable logistical regression analysis in our derivation cohort. The final model was tested in a separate validation cohort. Results The overall passing rate was 92% in our derivation cohort. Independent 12-lead ECG characteristics associated with AST passing were QRS ≤ 130 ms, absence of QRS/T discordance in lead II and R/T-ratio ≥3.5 in lead II. Eighty-three of 254 patients (33%) fulfilled these three criteria and had a passing rate of 100%. Of the validation cohort, 37 of 60 patients (62%) fulfilled all three criteria and also had a passing rate of 100%. The interobserver agreement for applying the ECG model was 90% (Cohen's Kappa = 0.80). Conclusion Using the standard 12-lead ECG, we developed a simple screening model with a high specificity for S-ICD eligibility. Our results suggest that patients who fulfill the three ECG criteria do not need additional AST-screening.

Myocardial perfusion imaging (MPI) using single-photon emission computed tomography (SPECT) is useful in the evaluation of cardiac allograft vasculopathy (CAV) in heart transplant (HTx) recipients. The current study evaluated the long-term prognostic value of stress SPECT MPI for predicting all-cause mortality and cardiac events in HTx recipients. The study population consisted of 166 HTx recipients (mean age 54 ± 10 years, 84% male) who underwent exercise or dobutamine stress 99mTc-tetrofosmin SPECT MPI for the assessment of CAV. An abnormal SPECT MPI was defined as the presence of a fixed or a reversible perfusion defect. Endpoints were all-cause mortality, cardiac mortality, and non-fatal myocardial infarction (MI). MPI abnormalities were detected in 55 patients (33%), including fixed defects in 28 patients (17%), partially reversible in 17 patients (10%), and completely reversible defects in 10 patients (6%). During a median follow-up of 12.8 years (range 0-15, mean follow-up 9.5 years), 109 (66%) patients died (all-cause mortality), of which 67 (40%) were due to cardiac causes. A total of 5 (3%) patients experienced a non-fatal MI. HTx recipients with a normal stress 99mTc-tetrofosmin SPECT MPI had a significantly better prognosis as compared with those with an abnormal study, up to 5 years after the initial test. The presence of a reversible perfusion defect was a significant predictor of all-cause mortality, cardiac mortality, and major cardiac events, during the entire follow-up period. Stress 99mTc-tetrofosmin SPECT MPI provides valuable prognostic information for the prediction of long-term outcome in HTx recipients. Patients with a normal stress 99mTc-tetrofosmin SPECT MPI have a significantly better prognosis as compared with those with an abnormal study, up to 5 years after initial testing.

Background The manufacturer has developed a new ECG screening tool to determine eligibility for the subcutaneous ICD (S-ICD), the “automatic screening tool” (AST), which may render manual ECG-screening unnecessary. The aim of the study was to determine the eligibility for the S-ICD using two methods (manual ECG-screening versus AST) in different patient categories including patients with cardiomyopathy, congenital heart disease and inherited primary arrhythmia syndrome. Methods We prospectively evaluated the ECG suitability for an S-ICD in consecutive patients at our outpatient clinic between February and June 2017. The primary endpoint of the study was ECG eligibility defined as at least 1 successful vector in both supine and sitting postures. Results A total of 254 patients (167 men; mean age 45 ± 16 years) were screened using both methods. Overall, there was a high ECG eligibility using either method (93% versus 92%, P = 0.45). Overall agreement between both methods was 94%. Patients with hypertrophic cardiomyopathy (HCM) more often had a failed screening test using either test in comparison to the patients without HCM (manual: odds ratio [OR] 3.3, 95% confidence interval [CI] 1.2–9.3, P = 0.02; AST: OR 3.0, 95% CI 1.2–7.6, P = 0.02). Conclusion AST showed a high agreement with manual ECG-screening for S-ICD. Overall there was a high ECG eligibility for S-ICD, although patients with HCM had a lower passing rate irrespective of the screening method.

Background: Sex disparities are common in hypertrophic cardiomyopathy (HCM). Previous research has shown that at time of myectomy, women are older, have greater impairment of diastolic function and more advanced cardiac remodeling. The clinical impact of these differences is unknown. Method: This study included 162 HCM patients (61% men) who underwent septal myectomy. Time to treatment was calculated in relation to symptom onset and diagnosis. Pre- and post-operative echocardiographic data were collected. Sex differences were assessed at baseline and in time-to-event survival analyses for the composite endpoint of all-cause mortality, cardiac transplantation, re-intervention and aborted sudden cardiac death. Results: Women were generally older at time of myectomy (57 vs. 49 years, p < 0.01), with similar time to treatment as measured from symptom onset (2.3 [1.3–6.0] vs. 2.8 [1.1–5.3] years, p > 0.05), but a shorter time since diagnosis compared to men (2.6 [1.2–7.0] vs. 4.3 [2.4–8.3] years, p = 0.02). Mean wall thickness and left atrial diameter were the same for men and women, but were higher in women when correcting for body surface area (absolute: 20 vs. 19 mm, 48 vs 46 mm, p ≥ 0.05; corrected: 9.7 vs. 11.2 mm/m2, 23.4 vs. 26.3 mm/m2, p < 0.01). After 5.9 [3.0–9.1] years, 15% of men and 8% of women had reached the composite endpoint (p > 0.05). Conclusion: In conclusion, although women present later in life and seem to have more advanced disease on echocardiography, time until myectomy was similar and clinical outcomes after myectomy are favourable for both men and women.

Background Shear waves are generated by the closure of the heart valves. Significant differences in shear wave velocity have been found recently between normal myocardium and disease models of diffusely increased muscle stiffness. In this study we correlate in vivo myocardial shear wave imaging (SWI) with presence of scarred tissue, as model for local increase of stiffness. Stiffness variation is hypothesized to appear as velocity variation. Methods Ten healthy volunteers (group 1), 10 hypertrophic cardiomyopathy (HCM) patients without any cardiac intervention (group 2), and 10 HCM patients with prior septal reduction therapy (group 3) underwent high frame rate tissue Doppler echocardiography. The SW in the interventricular septum after aortic valve closure was mapped along two M-mode lines, in the inner and outer layer. Results We compared SWI to 3D echocardiography and strain imaging. In groups 1 and 2, no change in velocity was detected. In group 3, 8/10 patients showed a variation in SW velocity. All three patients having transmural scar showed a simultaneous velocity variation in both layers. Out of six patients with endocardial scar, five showed variations in the inner layer. Conclusion Local variations in stiffness, with myocardial remodeling post septal reduction therapy as model, can be detected by a local variation in the propagation velocity of naturally occurring shear waves.

Aims Patients with a left ventricular assist device (LVAD) are challenging to evaluate using conventional imaging techniques, such as standard echocardiography (SE). The aim of this pilot study was to evaluate the potential of contrast echocardiography (CE) for the evaluation of the left ventricle (LV). Methods and results This prospective study included 14 ambulatory patients (mean age 58 ± 9 years, 79% male) with a LVAD (all HeartMate 3, Abbott Laboratories, Chicago, IL, USA). Nine (64%) patients had an ischaemic cardiomyopathy, and 5 (36%) had a non-ischaemic cardiomyopathy. All patients underwent SE and CE using intravenous administration of Sonovue contrast agent (Bracco, Milan, Italy). The echocardiograms were assessed by three observers, using a standard 17-segment model of the LV. Left ventricular end-diastolic volume (LVEDV) was assessed using the biplane Simpson method. The contrast agent was well tolerated by all patients, without any side effects. Overall, SE allowed visualization of 57% of LV segments (135/238) and CE allowed visualization of 79% of LV segments (187/238), P < 0.001. Per patient, SE resulted in visualization of 9.6 ± 5.2 segments and CE was able to visualize 13.4 ± 5.8 segments (P < 0.001). Administration of contrast agent significantly improved the assessment of LVEDV (feasibility SE: 36% vs. CE: 79%, P < 0.05). Conclusion Routine use of a contrast agent appears safe when used in patients having a new third generation LVAD and may enhance the diagnostic accuracy of transthoracic echocardiography in these patients. LV size determination can be obtained more often due to improved LV visualization using contrast agent.

Purpose Previous studies suggest that anterior mitral valve leaflet (AMVL) elongation is a primary phenotypic feature in hypertrophic cardiomyopathy (HCM). Our aim was to assess AMVL length in individuals with HCM gene mutations and in healthy controls and to identify predictors of the development of HCM during follow-up. Methods A total of 133 HCM mutation carriers and 135 controls underwent cardiac examination including electro- and echocardiography. AMVL length was measured in the parasternal long axis and apical three chamber view during diastole. Univariate and multivariable cox proportional hazard regression analyses were performed to identify predictors of HCM. Results There were no significant differences between HCM mutation carriers and controls regarding age and sex. In the parasternal long axis view, AMVL length was similar in mutation carriers and controls (24 ± 4 vs 24 ± 4 mm, p = 0.8). In the apical three chamber view, AMVL were shorter in mutation carriers (29 ± 4 vs 30 ± 4 mm, p = 0.02). When averaged for both views, AMVL length was similar in mutation carriers and controls (27 ± 3 vs 27 ± 3 mm, p = 0.2). During 5.8 ± 3.0 years follow-up, 13 (14%) HCM mutation carriers developed HCM. Pathological Q wave (hazard ratio 9.89, p = 0.004), E/e′ ratio (hazard ratio 2.52, p = 0.001), and maximal wall thickness (hazard ratio 2.15, p = 0.001) were independent predictors of HCM. AMVL length was not predictive of the development of HCM. Conclusions AMVL length is similar in HCM mutation carriers and controls. AMVL length is not predictive of the development of HCM, in contrast to pathological Q wave, E/e′ ratio, and maximal wall thickness.

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.

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.

In cardiac high-frame-rate color tissue Doppler imaging (TDI), a wave-like pattern travels over the interventricular septum (IVS) after atrial contraction. The propagation velocity of this myocardial stretch post-atrial contraction (MSPa) was proposed as a measure of left ventricular stiffness. The aim of our study was to investigate the MSPa in patients with hypertrophic cardiomyopathy (HCM) compared with healthy volunteers. Forty-two healthy volunteers and 33 HCM patients underwent high-frame-rate (500 Hz) TDI apical echocardiography. MSPa was visible in TDI, M-mode and speckle tracking. When assuming a wave propagating with constant velocity, MSPa in healthy volunteers (1.6 ± 0.3 m/s) did not differ from that in HCM patients (1.8 ± 0.8 m/s, p = 0.14). Yet, in 42% of patients with HCM, the MSPa had a non-constant velocity over the wall: in the basal IVS, the velocity was lower (1.4 ± 0.5 m/s), and in the mid-IVS, much higher (6.1 ± 3.4 m/s, p0.0001), and this effect was related to the septal thickness. The reason is hypothesized to be the reaching of maximal longitudinal myocardial distension in HCM patients.

Objectives This study sought to summarize the clinical outcome of implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada syndrome. Background Brugada syndrome is characterized by cardiac conduction abnormalities and a high risk of ventricular arrhythmias that may result in sudden cardiac death. A complete overview of clinical outcome, appropriate and inappropriate interventions, and complications after ICD therapy in patients with Brugada syndrome is lacking. Methods The online MEDLINE database was searched for published reports and yielded 828 studies on outcome and complications after ICD therapy in patients with Brugada syndrome. After careful evaluation, 22 studies including a total of 1,539 patients were included in the meta-analysis. Results In total, 1,539 patients (mean age 45 years, 18% women) underwent ICD implantation for primary (79%) or secondary (21%) prevention of sudden cardiac death. During a mean follow-up of 4.9 years, the appropriate and inappropriate ICD intervention rates were 3.1 and 3.3 per 100 person-years, respectively. The cardiac mortality rate was 0.03 per 100 person-years and noncardiac mortality rate was 0.3 per 100 person-years. ICD-related complications per 100 person-years consisted of lead malfunction (1.6), psychological complication (1.3), infection (0.6), lead dislocation (0.4), and any complication (0.6). Conclusions Patients with Brugada syndrome judged to be at high risk for ventricular arrhythmia may significantly benefit from ICD therapy, which is associated with an appropriate ICD intervention rate of 3.1 per 100 person-years and low cardiac and noncardiac mortality rates. Inappropriate ICD interventions and ICD-related complications may lead to considerable morbidity.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder. It is mainly caused by mutations in genes encoding sarcomere proteins. Mutant forms of these highly abundant proteins likely stress the protein quality control (PQC) system of cardiomyocytes. The PQC system, together with a functional microtubule network, maintains proteostasis. We compared left ventricular (LV) tissue of nine donors (controls) with 38 sarcomere mutation-positive (HCMSMP) and 14 sarcomere mutation-negative (HCMSMN) patients to define HCM and mutation-specific changes in PQC. Mutations in HCMSMP result in poison polypeptides or reduced protein levels (haploinsufficiency, HI). The main findings were 1) several key PQC players were more abundant in HCM compared to controls, 2) after correction for sex and age, stabilizing heat shock protein (HSP)B1, and refolding, HSPD1 and HSPA2 were increased in HCMSMP compared to controls, 3) &alpha, tubulin and acetylated &alpha, tubulin levels were higher in HCM compared to controls, especially in HCMHI, 4) myosin-binding protein-C (cMyBP-C) levels were inversely correlated with &alpha, tubulin, and 5) &alpha, tubulin levels correlated with acetylated &alpha, tubulin and HSPs. Overall, carrying a mutation affects PQC and &alpha, tubulin acetylation. The haploinsufficiency of cMyBP-C may trigger HSPs and &alpha, tubulin acetylation. Our study indicates that proliferation of the microtubular network may represent a novel pathomechanism in cMyBP-C haploinsufficiency-mediated HCM.

Pathogenic gene mutations are found in about 50% of patients with hypertrophic cardiomyopathy (HC). Previous studies have shown an association between sarcomere mutations and medium-term outcome. The association with long-term outcome has not been described. The aim of this cohort study was to assess the long-term outcomes of patients with genotype positive (G+) and genotype negative (G-) HC. The study population consisted of 626 patients with HC (512 probands and 114 relatives) who underwent phenotyping and genetic testing from 1985 to 2014. End points were all-cause mortality, cardiovascular (CV) mortality, heart failure (HF)-related mortality, and sudden cardiac death/aborted sudden cardiac death (SCD/aborted SCD). Kaplan-Meier and multivariate Cox regression analyses were performed. A pathogenic mutation was detected in 327 patients (52%). G+ probands were younger than G- probands (46 ± 15 vs 55 ± 15 years, p0.001), had more non sustained ventricular tachycardia (34% vs 13%; p0.001), more often a history of syncope (14% vs 7%; p = 0.016), and more extreme hypertrophy (maximal wall thickness ≥30 mm, 7% vs 1%; p0.001). G- probands were more symptomatic (New York Heart Association ≥II, 73% vs 53%, p0.001) and had higher left ventricular outflow tract gradients (42 ± 39 vs 29 ± 33 mm Hg, p = 0.001). During 12 ± 9 years of follow-up, G+ status was an independent risk factor for all-cause mortality (hazard ratio [HR] 1.90, 95% CI 1.14 to 3.15; p = 0.014), CV mortality (HR 2.82, 95% CI 1.49 to 5.36; p = 0.002), HF-related mortality (HR 6.33, 95% CI 1.79 to 22.41; p = 0.004), and SCD/aborted SCD (HR 2.88, 95% CI 1.23 to 6.71; p = 0.015). In conclusion, during long-term follow-up, patients with G+ HC are at increased risk of all-cause death, CV death, HF-related death, and SCD/aborted SCD.

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.

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.

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

It is not entirely clear whether ischemia burden on stress single-photon emission computed tomography (SPECT) effectively identifies patients who have a long-term benefit from coronary revascularization. The study population consisted of 719 patients with ischemia on stress SPECT. Early coronary revascularization was defined as percutaneous coronary intervention or coronary artery bypass grafting ≤90 days after SPECT. Patients who underwent late revascularization (>90 days after SPECT) were excluded (n = 164). Of the 538 patients (73% men, mean age 59.8 ± 11 years), 348 patients had low ischemia burden (

Background: Contemporary hypertrophic cardiomyopathy (HCM) family screening includes clinical evaluation and genetic testing (GT). This screening strategy requires the identification of a pathogenic mutation in the proband. Our aim was to examine the results of this HCM screening strategy. Methods: Between 1985 and 2016, 777 relatives of 209 probands were assessed in the context of HCM screening. Genotype-positive (G+) relatives and relatives without genetic testing (GT) underwent repeated clinical evaluations. In genotype-negative (G-) relatives mortality was assessed during follow-up. Results: A pathogenic mutation was identified in 72% of probands. After counseling, GT was performed in 620 (80%) relatives: 264 (43%) were G+ (age 41±18 y) and 356 (57%) were G- (age 48±17 y). At first screening, HCM was diagnosed in 98 (37%) G+ relatives and 28 (17%) relatives without GT ( p p =0.8), and 100%/100% in relatives without GT. Conclusions: HCM was identified in 30% of relatives at first screening, and 16% developed HCM during 7 years of repeated evaluation. GT led to a discharge from clinical follow-up in 46% of the study population. Survival in the relatives was good.

Purpose In patients with structural heart disease (SHD) or inherited primary arrhythmia syndrome (IPAS), the occurrence of unexplained syncope or palpitations can be worrisome as they are at increased risk of sudden cardiac death. An implantable loop recorder (ILR) can be a useful diagnostic tool. Our purpose was to compare the diagnostic yield, arrhythmia mechanism, and management in patients with SHD, patients with IPAS, and those without heart disease. Methods Retrospective single-center study in consecutive patients who underwent an ILR implantation. Results Between March 2013 and December 2016, a total of 94 patients received an ILR (SHD, n = 20; IPAS, n = 14; no SHD/IPAS, n = 60). The type of symptoms at the time of implantation was similar between groups. During a median follow-up of 10 months, 45% had an ILR-guided diagnosis. Patients with IPAS had a lower diagnostic yield (14%) in comparison to the other groups (no SHD/IPAS 47%, P = 0.03; SHD 60%, P = 0.01, respectively). Furthermore, patients with SHD had a higher incidence of nonsustained VT in comparison to patients without SHD/IPAS (30 versus 3%, P

Gender has been proposed to impact the phenotype and prognosis of hypertrophic cardiomyopathy (HC). Our aims were to study gender differences in the clinical presentation, phenotype, genotype, and outcome of HC. This retrospective single-center cohort study included 1,007 patients with HC (62% male, 80% genotyped) evaluated between 1977 and 2017. Hazard ratios (HR) were calculated using multivariable Cox proportional hazard regression models. At first evaluation, female patients presented more often with symptoms (43% vs 35%, p = 0.01), were older than male patients (56 ± 16 vs 49 ± 15 years, p

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

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. (C) 2015 by the American College of Cardiology Foundation.

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. 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. The mean age of patients was 60 +/- A 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. 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.

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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Background Hypertrophic cardiomyopathy (HC) is characterized by left ventricular (LV) hypertrophy and associated with papillary muscle (PM) abnormalities. The aim of this study was to evaluate the utility of three-dimensional echocardiography (3DE) for the geometric assessment of LV hypertrophy and PM morphology. Methods The study included 24 patients with an established diagnosis of HC and 31 healthy controls. 3DE was performed using an iE33 or EPIQ 7C ultrasound system with an X5-1 transducer. QLAB software was used for the 3D analysis of LV wall thickness (LVWT) and PM morphology and hypertrophy; the number and cross-sectional area (CSA) of anterolateral and posteromedial PMs; and the presence of bifid or accessory PMs. Results Patients with HC had a larger LVWT compared to controls in all segments (p

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 rho = 0.719, rho = 0.538, rho = 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.

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.

Aims Carotid contrast-enhanced ultrasound (CEUS) was recently proposed for the evaluation of large-vessel vasculitides (LVV), particularly to assess vascularization within the vessel wall. The aim of this pilot study was to evaluate the potential of carotid colour Doppler ultrasound (CDUS) and CEUS in patients with LVV. Methods and results This prospective study included seven patients (mean age 48 +/- 14 years, all females) with established LVV (Takayasu arteritis or giant cell arteritis). All patients underwent CDUS and CEUS (14 carotid arteries). Intima-media thickness, lumen diameter, Doppler velocities, vessel wall thickening, and lesion thickness were assessed. CEUS was used to improve visualization of the lumen-to-vessel wall border, and to visualize carotid wall vascularization. Four (57%) patients [7 (50%) carotid arteries] exhibited lesions, and the average lesion thickness was 2.0 +/- 0.5 mm. According to the Doppler peak systolic velocity, 5 (35%) carotid arteries had a = 70% stenosis. The contrast agent improved the image quality and the definition of the lumen-to-vascular wall border. Carotid wall vascularization was observed in 5 (71%) patients [9 (64%) carotid arteries]. Five (36%) carotid arteries had mild-to-moderate vascularization, and 4 (29%) had severe wall vascularization. Conclusion Carotid CDUS allows the assessment of anatomical features of LVV, including vessel wall thickening and degree of stenosis. Carotid CEUS improves the visualization of the lumen border, and allows dynamic assessment of carotid wall vascularization, which is a potential marker of disease activity in patients with LVV.

Previous data have indicated that carotid plaque ulceration is a strong predictor of cerebrovascular events. Standard ultrasound and color Doppler ultrasound (CDUS) scans have poor diagnostic accuracy for the detection of carotid plaque ulceration. The aim of the present prospective study was to assess the value of contrast-enhanced ultrasound (CEUS) scans for the detection of carotid plaque ulceration. The Institutional Ethics Committee approved the study protocol, and all patients provided informed consent. The patients had symptomatic stenosis of the internal carotid artery and underwent carotid computed tomographic angiography as part of their clinical evaluation. All patients underwent a CDUS examination in conjunction with CEUS. Carotid plaque ulceration was defined as the presence of >= 1 disruptions in the plaque-lumen border >= 1 x 1 mm. Carotid computed tomographic angiography was used as reference technique. The study population consisted of 20 patients (mean age 64 +/- 9 years, 80% men), and 39 carotid arteries were included in the present analysis. Computed tomographic angiography demonstrated that the plaque surface was smooth in 15 (38%), irregular in 7 (18%) and ulcerated in 17 (44%) carotid arteries. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CDUS for the detection of ulceration was 29%, 73%, 54%, 46%, and 57%, respectively. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of CEUS for the detection of ulceration was 88%, 59%, 72%, 63%, and 87%, respectively. CEUS had superior sensitivity and diagnostic accuracy for the assessment of carotid plaque ulceration compared with CDUS. CEUS improved the intrareader and inter-reader variability for the assessment of carotid plaque ulceration compared with CDUS. In conclusion, CEUS could be an additional method for the detection of carotid plaque ulceration. The role of CDUS for the assessment of carotid plaque ulceration seems limited. (C) 2013 Elsevier Inc. All rights reserved.

Objective B-mode ultrasound measurement of the carotid intima-media thickness (CIMT) is a widely used marker for atherosclerosis and is associated with future cardiovascular events. This article provides a review and meta-analysis of the published evidence on the association of CIMT with future cardiovascular events and its additional value to traditional cardiovascular risk prediction models. Methods A systematic review and meta-analysis of the evidence on the association of CIMT with future cardiovascular events and the additional value of CIMT to traditional cardiovascular risk prediction models was conducted. The association of CIMT with future cardiovascular events and the additional value of CIMT were calculated using random effects analysis. Results The literature search yielded 1196 articles of which 15 articles provided sufficient data for the meta-analysis. A 1 SD increase in CIMT was predictive for myocardial infarction (HR 1.26, 95% CI 1.20–1.31) and for stroke (HR 1.31, 95% CI 1.26–1.36). A 0.1 mm increase in CIMT was predictive for myocardial infarction (HR 1.15, 95% CI 1.12–1.18) and for stroke (HR 1.17, 95% CI 1.15–1.21). The overall performance of risk prediction models did not significantly increase after addition of CIMT data. The areas under the curve increased from 0.726 to 0.729 ( p = 0.8). Conclusions CIMT as measured by B-mode ultrasound is associated with future cardiovascular events. However, the addition of CIMT to traditional cardiovascular risk prediction models does not lead to a statistical significantly increase in performance of those models.

Previous studies have reported a favorable outcome of patients with normal single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). The aim of this study was to assess the very long-term prognosis of patients with known coronary artery disease (CAD) and normal SPECT MPI results. The population consisted of 266 patients with known CAD (defined as a healed myocardial infarction and/or a previous coronary revascularization), who underwent exercise bicycle or dobutamine-atropine stress SPECT MPI and had normal perfusion during stress and at rest. End points during follow-up were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction. Univariate and multivariate analyses were performed to identify predictors of long-term outcome. Follow-up was completed in 261 (98%) patients. During a median follow-up of 12 years, 94 (36%) patients died, of which 26 (10%) died due to cardiac causes, and 15 (6%) had a nonfatal myocardial infarction. The annualized mortality rate was 3.1%, annualized cardiac mortality rate was 0.9%, and the annualized event rate for cardiac death and/or nonfatal infarction was 1.2%. Independent predictors of total mortality were age, diabetes mellitus, and rate-pressure product at peak stress. Independent predictors of cardiac mortality were age, male gender, and rate-pressure product at peak stress. Patients with known CAD and a normal SPECT MPI study have a favorable long-term prognosis. Clinical and stress test variables can be used to identify patients with a higher risk status.

Background— Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a cardiomyopathy characterized by ventricular arrhythmias and an abnormal right ventricle. Implantable cardioverter defibrillator (ICD) therapy may prevent sudden cardiac death in patients with ARVD/C. Currently, an overview of outcomes, appropriate and inappropriate interventions, and complications of ICD therapy in ARVD/C is lacking. Methods and Results— A literature search was performed to identify studies reporting outcome and complications in patients with ARVD/C who underwent ICD implantation. Of 641 articles screened, 24 studies on 18 cohorts were eligible for inclusion. In case of multiple publications on a cohort, the most recent publication was included in the meta-analysis. There were 610 patients (mean age, 40.4 years; 42% women), who had an ICD for primary or secondary prevention of sudden cardiac death. Risk factors for sudden cardiac death were presyncope (61%), syncope (31%), previous cardiac arrest (14%), ventricular tachycardia (58%), and ventricular fibrillation (6%). Antiarrhythmic medication consisted mostly of β-blockers (38%), amiodarone (14%), or sotalol (30%). During the 3.8-year follow-up, annualized cardiac mortality rate was 0.9%, annualized noncardiac mortality rate was 0.8%, and annualized heart transplant rate was 0.9%. The annualized appropriate and inappropriate ICD intervention rates were 9.5% and 3.7%, respectively. ICD-related complications consisted of difficult lead placement (18.4%), lead malfunction (9.8%), infection (1.4%), lead displacement (3.3%), and any complication (20.3%). Conclusions— Cardiac and noncardiac mortality rates after ICD implantation in patients with ARVD/C are low. Appropriate ICD interventions occur at a rate of 9.5%/y. Inappropriate ICD interventions and complications lead to considerable ICD-related morbidity.

Cardiovascular risk stratification of asymptomatic patients is based on the assessment of risk factors. Noninvasive imaging of subclinical atherosclerosis may improve cardiovascular risk stratification, especially in patients with co-morbidities. The aim of this study was to investigate the effect of contrast-enhanced ultrasound (CEUS) of the carotid arteries on cardiovascular risk assessment. The study population consisted of 100 consecutive asymptomatic patients with >= 1 clinical risk factor for atherosclerosis. Cardiovascular risk was estimated by calculating the Prospective Cardiovascular Munster Heart Study (PRO-CAM) risk score. This score was divided into 3 subgroups: low (= 20%). Subclinical carotid atherosclerosis was assessed using standard ultrasound for intima-media thickness and plaque screening and CEUS for additional plaque screening. CEUS was performed using SonoVue contrast agent. Patients with subclinical atherosclerosis were considered to be at high cardiovascular risk. McNemar's test was used to compare PROCAM score to ultrasound findings. The mean PROCAM risk score was 9 +/- 10; the PROCAM risk score was low in 72 patients (72%), intermediate in 17 patients (17%), and high in 11 patients (11%). A total of 21 patients (21%) had abnormal carotid intima-media thickness, 77% had plaques on conventional carotid ultrasound, and 88% had plaques on standard carotid ultrasound combined with CEUS. Detection of atherosclerosis led to the reclassification of 79 patients (79%) to high cardiovascular risk (p

Background— MYBPC3 (Myosin-binding protein C) founder mutations account for 35% of hypertrophic cardiomyopathy (HCM) cases in the Netherlands. We compared clinical characteristics and outcome of MYBPC3 founder mutation (FG+) HCM with nonfounder genotype-positive (G+) and genotype-negative (G−) HCM. Methods and Results— The study included 680 subjects: 271 FG+ carriers, 132 G+ probands with HCM, and 277 G− probands with HCM. FG+ carriers included 134 FG+ probands with HCM, 54 FG+ relatives diagnosed with HCM after family screening, 74 FG+/phenotype-negative relatives, and 9 with noncompaction or dilated cardiomyopathy. The clinical phenotype of FG+ and G+ probands with HCM was similar. FG+ and G+ probands were younger with less left ventricular outflow tract obstruction than G− probands, however, had more hypertrophy, and nonsustained ventricular tachycardia. FG+ relatives with HCM had less hypertrophy, smaller left atria, and less systolic and diastolic dysfunction than FG+ probands with HCM. After 8±6 years, cardiovascular mortality in FG+ probands with HCM was similar to G+ HCM (22% versus 14%; log-rank P =0.14), but higher than G− HCM (22% versus 6%; log-rank P P =0.009). Cardiac events were absent in FG+/phenotype-negative relatives; subtle HCM developed in 11% during 6 years of follow-up. Conclusions— Clinical phenotype and outcome of FG+ HCM was similar to G+ HCM but worse than G− HCM and FG+ HCM diagnosed in the context of family screening. These findings indicate the need for more intensive follow-up of FG+ and G+ HCM versus G− HCM and FG+ HCM in relatives.

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.

Background Exercise 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) is a useful tool for short- and medium-term risk stratifications. Currently, the long-term prognostic application of this technique has not been evaluated. Methods and Results Exercise 99mTc-tetrofosmin was performed in 655 consecutive patients. Ten patients who underwent revascularization

Aims The sensitivity of standard carotid ultrasound and colour Doppler for the detection of subclinical atherosclerotic plaques is suboptimal. The aim of this study is to assess whether contrast-enhanced ultrasound (CEUS) added to standard carotid ultrasound improves the detection of subclinical atherosclerosis. Methods and results Carotid intima–media thickness (CIMT) measurement, standard carotid ultrasound including colour Doppler imaging, and CEUS were performed in 100 asymptomatic patients with one or more risk factors for atherosclerosis. CEUS was performed using intravenous administration of SonoVue™ contrast agent (Bracco S.p.A., Milan, Italy). CIMT, standard ultrasound, colour Doppler, and CEUS were reviewed by two independent observers. Standard ultrasound, colour Doppler, and CEUS were scored for the presence of atherosclerotic plaques. Subclinical atherosclerosis was diagnosed if patients had a CIMT above their age-corrected threshold value or if atherosclerotic plaques were present on standard carotid ultrasound clips or CEUS clips. McNemar's test was performed to compare between groups. Twenty-one patients (21%) had a thickened CIMT value and were considered to have subclinical atherosclerosis. Standard carotid ultrasound including colour Doppler demonstrated atherosclerotic plaques in 77 patients (77%). The addition of CEUS to the standard ultrasound protocol demonstrated atherosclerotic plaques in 88 patients (88%). The incorporation of CEUS into the standard carotid ultrasound protocol resulted in a significantly improved detection of patients with subclinical atherosclerosis ( P < 0.01). Conclusion CEUS has an incremental value for the detection of subclinical atherosclerosis in the carotid arteries. Atherosclerotic plaques which were only detected with CEUS and not with standard carotid ultrasound and colour Doppler imaging were predominantly hypoechoic.

Purpose The purpose of this paper is to present a methodology to estimate the carotid artery lumen centerlines in ultrasound (US) images obtained in a free-hand examination. Challenging aspects here are speckle noise in US images, artifacts, and the lack of contrast in the direction orthogonal to the US beam direction. Method An algorithm based on a rough lumen segmentation obtained by robust ellipse fitting was developed to deal with these conditions and estimate the lumen center in 2D B-mode scans. In a free-hand sweep examination, continuous image acquisitions are performed through time when the radiologist moves the probe on the patient’s neck. The result is a series of images that show 2D cross-sections of the carotid’s morphology. A tracking sensor (Flock of Birds) was attached to the probe and both were connected to a PC executing the Stradwin software, which relates spatial information to the acquisition data of the US probe. The spatial information was combined with the 2D lumen center estimates to provide a centerline in 3D. For validation, 19 carotid scans from 15 different patients were scanned, their centerlines calculated by the algorithm and compared with results acquired by manual annotations. Results The average Euclidean distance between both among all the examinations was 0.82 mm. For each examination, the percentage of these Euclidean distances below 2 mm was calculated; the average over all examinations was 92%. Conclusion Automated 3D estimation of carotid artery lumen centerlines in free-hand real-time ultrasound is feasible and can be performed with high accuracy. The algorithm is robust enough to keep the centerlines inside the vessel, even in the absence of contrast in parts of the vessel wall.

modality rapidly expanded from diagnosing coronary artery disease (CAD) to risk stratification of patients undergoing vascular surgery; risk stratification of patients with chronic CAD, unstable angina, acute or chronic myocardial infarction (MI), or valvular heart disease; and the assessment of myocardial viability in patients with severe left ventricular (LV) dysfunction. Thus, dobutamine stress has been applied to progressively more complex, older, and higher-risk patients. Additionally, stress protocols became more aggressive, with higher dobutamine doses and the addition of atropine. 3 Although generally regarded as a safe stress modality, serious complications do occur. In this review, we will describe the incidence, pathophysiology, and treatment of complications during dobutamine-atropine stress echocardiography (DASE). Data on incidence of complications were obtained from 26 studies including 400 patients that reported at least the major complications of mortality, acute MI, ventricular fibrillation, and sustained ventricular tachycardia, 4–29 for a total of 55 071 patients (Table 1). In addition, references are given to case reports and studies dealing specifically with a particular complication.

Treating hyperglycemia may improve patient outcome, but is a clinical challenge. Three variations of a computerized insulin protocol were compared with regard to protocol compliance and achievement of glucose target levels. In group 1, the existing protocol was applied, in group 2 the protocol was modified to account for decreasing glucose values; group 3 had a higher threshold for initiating insulin, wider glucose target ranges, and included instructions to regulate glucose around mealtimes. From July 28, 2008 until February 1, 2010, data from 1255 patients admitted to our Intensive Cardiac Care Unit with at least 2 glucose measurements were analyzed. Mean age was 64 +/- 15 years, 66% were male, 21% had diabetes. Groups 1 to 3 included 269, 814, and 142 patients, respectively. Protocol compliance in group 2 was lower with 44% of the glucose measurements performed on time versus 51% in group 1 (P < 0.001), and insulin was dosed correctly in 57% versus 67% (P < 0.001). In group 3, compliance increased, 52% of the measurements were done on time, and insulin was dosed correctly in 71%. Average glucose levels increased in group 3 due to a higher threshold for starting insulin and a wider target range: 70% (group 1), 66% (group 2), and 61% (group 3) had an average glucose of

Objective To investigate the association between (cardiac) mortality and spatial QRS-T angle in patients undergoing dobutamine - atropine stress echocardiography (DSE) for evaluation of known or suspected coronary disease. Methods Between 1990 and 2003, 2347 patients underwent DSE for evaluation of coronary disease at the Erasmus Medical Center. Echocardiographic images were analyzed offline using a 16-segment, 5-point scoring model for regional function. Twelve-lead resting ECGs were analyzed and patients were grouped in three categories according to their spatial QRS-T angle: normal (0-105 degrees), borderline (105-135 degrees), and abnormal (135-180 degrees). Results Mean age was 61 +/- 13 years, 66% were male, 32% had hypertension, 26% had hypercholesterolemia, 28% were smokers, and 12% were diabetic. During a mean follow-up of 7 +/- 3.4 years, 26.5% (623) of the patients died; 15.3% (359) died due to a cardiac cause. Abnormal QRS-T angle (135-180 degrees) was present in 21% of the patients. Abnormal QRS-T angle was a predictor of cardiac death [ hazard ratio: 3.2 (2.6-4.1)] and all-cause mortality [hazard ratio: 2.2 (1.8-2.6)]. After multivariate analysis abnormal and borderline QRS-T angle, peak wall motion score, age, male sex, history of diabetes, history of heart failure, smoking, and hypertension were independent predictors of (cardiac) death. Conclusion Abnormal QRS-T angle is an independent predictor of (cardiac) death in patients undergoing DSE. Abnormal QRS-T angle should be considered as a risk factor in stable patients evaluated for coronary disease. Coron Artery Dis 21:26-32 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.