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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.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are frequently used for primary and secondary prevention in patients with cardiomyopathies due to different etiologies. However, long-term outcome studies in patients with noncompaction cardiomyopathy (NCCM) are scarce.OBJECTIVES: This study summarizes the long-term outcome of ICD therapy in patients with NCCM compared with those with dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM).METHODS: Prospective data from our single-center ICD registry were used to analyze the ICD interventions and survival in patients with NCCM (n = 68) compared with patients with DCM (n = 458) and patients with HCM (n = 158) from January 2005 to January 2018.RESULTS: This NCCM population with an ICD for primary prevention comprised 56 (82%) patients with a median age of 43 years and 52% males, compared with 85% in patients with DCM and 79% in patients with HCM (P = 0.20). During a median follow-up of 5 years (IQR: 2.0-6.9 years), appropriate and inappropriate ICD interventions were not significantly different. Nonsustained ventricular tachycardia during Holter monitoring in patients with NCCM was the only significant risk factor for appropriate ICD therapy in patients with NCCM, with a HR of 5.29 (95% CI: 1.12-24.96). The long-term survival was significantly better in the univariable analysis in the NCCM group. However, there was no difference in multivariable Cox regression analyses between the cardiomyopathy groups.CONCLUSIONS: At 5 years of follow-up, the rate of appropriate and inappropriate ICD interventions in NCCM was comparable to that in DCM or HCM. In multivariable analysis, no differences in survival were found between the cardiomyopathy groups.

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.

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.

Funding Acknowledgements Type of funding sources: None. Genetic testing in relatives of hypertrophic cardiomyopathy (HCM) patients can lead to early identification of carriers of pathogenic DNA variants (G+), before onset of left ventricular hypertrophy (LVH). Repeated evaluation by electrocardiography (ECG) and transthoracic echocardiography (TTE) is recommended to detect HCM during follow-up. Cardiovascular magnetic resonance (CMR) imaging has become valuable in the work-up of HCM, although its role in G+ subjects has not been extensively evaluated. In this study, we investigated the value of CMR in the G+/LVH- population. We included 55 G+ subjects who underwent CMR in addition to ECG and TTE, with a maximal wall thickness (MWT) An overview of ECG/TTE and CMR findings is shown in the Figure. Two of 16 (13%) subjects diagnosed with HCM on TTE were reclassified as having no HCM on CMR, and 8 of 39 (21%) subjects without HCM on TTE were reclassified as HCM on CMR. These 8 subjects had a mean MWT of 15.4 ± 2.6 mm on CMR and a mean MWT difference of 4.5 ± 2.9 mm (range 1.7-9.4) compared to TTE, which in 3 cases was explained by a hook-shaped thickening of the basal anterior wall in the 2 chamber view, not visible on TTE. Compared to subjects without HCM on both modalities, the reclassified group had a significantly higher QRS duration (104 ± 14 vs 93 ± 11 ms, p = 0.03) and anterior mitral valve leaflet length (30 ± 4 vs 26 ± 3 mm, p = 0.01). Of the 13 subjects with normal ECG/TTE results, none were reclassified as HCM using CMR. The proportion of additional CMR abnormalities was large in subjects with and without abnormal ECG/TTE results (57% vs 38%, p = 0.24). Subjects with poor TTE image quality were equally likely to be reclassified compared to those with sufficient image quality (10% vs 24%, p = 0.19). Logistic regression demonstrated that the presence of TTE/ECG abnormalities (odds ratio [OR] 8.7 [1.3-59.0], p = 0.03) and age (OR 1.1 [1.0-1.2], p Additional CMR imaging reclassifies 18% of subjects. Subjects with normal ECG and TTE results are not diagnosed as HCM on CMR, but the prevalence of HCM-related abnormalities on CMR was high in subjects with and without ECG/TTE abnormalities. Abstract Figure. Diagnostic approach and CMR findings

Funding Acknowledgements Type of funding sources: None. Carriers of pathogenic DNA variants (G+) causing hypertrophic cardiomyopathy (HCM) can be identified by genetic testing, before manifestation of left ventricular hypertrophy (LVH). These G+/LVH- subjects are routinely monitored for phenotypic expression, which, alongside LVH, can include other HCM-related abnormalities, including crypts and myocardial fibrosis. Cardiovascular magnetic resonance (CMR) imaging has emerged as a valuable technique in diagnosing and follow-up of HCM. In this study, we identified clinical features of subclinical HCM in a G+/LVH- population compared to healthy subjects. We studied 33 G+ subjects with CMR and a maximal wall thickness (MWT) G+ subjects had a higher MWT (10.9 ± 1.6 vs 10.2 ± 1.3 mm, p = 0.04), a similar interventricular septal wall (IVS) thickness (8.8 ± 1.6 vs 8.7 ± 1.6 mm, p = 0.85), a smaller posterior wall (PW) and a higher IVS/PW ratio (6.6 ± 1.2 vs 7.7 ± 1.3mm, p CMR demonstrates significant morphological differences between the G+/LVH- population and healthy controls. Further studies are needed to assess the prognostic significance of these morphological features. Predictors of genotype-positive status Variables G+ subjects (n = 33) Controls (n = 35) P value OR for G+ status P value Left ventricular mass/BSA (g/m²) 45 ± 7.4 53 ± 7.9

Background Cardiac sarcoidosis (CS) is associated with poor prognosis, making early diagnosis and treatment important. The aim of this study is to evaluate our diagnostic results and follow-up for the diagnosis of CS in a tertiary center. Methods We studied 188 patients with proven extra-cardiac sarcoidosis referred to our outpatient clinic for evaluation of cardiac involvement. Eight patients were excluded because electrocardiogram (ECG) and/or transthoracic echocardiography (TTE) was missing. Cardiac magnetic resonance (CMR) and/or positron emission tomography (PET) was performed in 66% and 37% of the patients, respectively. Median follow-up duration was 2.9 [1.2–5.3] years. The diagnosis of CS was based on the Heart Rhythm Society criteria. Results Cardiac symptoms defined as palpitations, angina, dyspnea and (near)-syncope were present in 156 of 180 (87%) patients. Any abnormality on ECG (bundle branch blocks, atrioventricular blocks, sinus tachycardia or atrial fibrillation) and/or TTE (left ventricular ejection fraction Conclusions In our study, 23% of the patients with proven extra-cardiac sarcoidosis was diagnosed with CS. Cardiac symptoms, ECG and TTE were of limited diagnostic value for screening for CS. CMR provided a good diagnostic yield and identified other cardiac diseases in a substantial number of patients. Figure 1. KMCurve_CompositeEndpoint Funding Acknowledgement Type of funding source: None

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.

Funding Acknowledgements None. The presence and magnitude of left ventricular outflow tract (LVOT) obstruction in hypertrophic obstructive cardiomyopathy (HOCM) patients is weakly associated with presence of symptoms. The factors underlying this are not well understood. We hypothesize that time to peak velocity (TPV) of LVOT flow is associated with symptomatic status. We included 136 HOCM patients (58% men, mean age 55 ± 14 years) with peak gradients ≥30 mmHg at rest or during Valsalva without aortic valve stenosis. At rest and during Valsalva, continuous wave Doppler tracings from 3 consecutive beats were used to assess peak velocity (PV), left ventricular ejection time (LVET) and TPV, which was defined as the time interval between the onset of flow over the LVOT and the moment of PV. Differences were compared between asymptomatic and symptomatic patients (defined as New York Heart Association class I vs. II-IV). The relation between symptom status and TPV was investigated using logistic regression models. A random sample of 20 patients was examined by 2 observers and reproducibility was assessed using the intraclass correlation coefficient (ICC). Symptomatic patients were more often female (table) and had significantly higher mean TPV values (figure). In multivariable logistic regression models, TPV was an independent predictor of symptomatic status after correction for PV, LVOT diameter, heart rate and age (odds ratio 1.02 per 1 ms, p Delayed TPV is associated with symptomatic status in HOCM patients, after adjustment for heart rate, peak velocity, LVOT diameter and age, and is an easily measured echocardiographic variable with excellent inter-reader reproducibility. The clinical implications of delayed TPV, particularly in the context risk prediction and clinical decision making, remain to be determined. Characteristics per group Asymptomatic HOCM patients n = 47 Symptomatic HOCM patients n = 89 p value Age, y 55 ± 14 55 ± 14 0.99 Male gender 34 (72%) 45 (51%) 0.01 Body mass index, kg/m² 27 ± 5 28 ± 5 0.08 Left atrial diameter, mm 46 ± 7 47 ± 7 0.64 Septal wall thickness, mm 18 ± 4 19 ± 5 0.58 LV outflow tract diameter, mm 22 ± 3 21 ± 3 0.001 Peak velocity, cm/s 403 ± 86 434 ± 79 0.03 LV ejection time, ms 316 ± 44 340 ± 42 0.002 Time to peak velocity, ms 157 ± 32 178 ± 32 Abstract P802 Figure. Time to peak velocity per NYHA class

Background Family screening for hypertrophic cardiomyopathy (HCM) is based on genetic testing and clinical evaluation (maximal left ventricular wall thickness (MWT) ≥15 mm, or ≥13 mm in first-degree relatives of HCM patients). The aim of this study was to assess the effect of gender and body size on diagnosis of HCM and prediction of clinical outcome. Methods This study includes 199 genotype-positive subjects (age 44 ± 15 years, 50% men) referred for cardiac screening. Gender-specific reference values for MWT indexed by body surface area (BSA), height and weight were derived from 147 healthy controls. Predictive accuracy of each method for HCM-related events was assessed by comparing areas under the receiver operating characteristic curves (AUC). Results Men had a higher absolute, but similar BSA- and weight-indexed MWT compared with women (14.0 ± 3.9 mm vs 11.5 ± 3.8 mm, p 2 vs 6.6 ± 2.4 mm/m2; 0.17 ± 0.06 mm/kg vs 0.17 ± 0.06 mm/kg, both p > 0.05). Applying BSA- and weight-indexed cut-off values decreased HCM diagnoses in the study group (48% vs 42%; 48% vs 39%, both p 2: 58% vs 45%; ≤70 kg: 37% vs 46%; ≥85 kg: 53% vs 25%, all p p Conclusions In genotype-positive subjects referred for family screening, differences in MWT across gender are mitigated after indexation by BSA or weight. Indexation decreases the prevalence of HCM, particularly in larger men, and improves the predictive accuracy for HCM-related events.

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.

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). Objective To determine 12-lead ECG characteristics 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 prospectively 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 (Table). 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). Table 1 Variables Univariable Multivariable OR (95% CI) P-value OR (95% CI) P-value QRS ≤130 ms 9.65 (3.66–25.43) Figure 1 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. Therefore, we developed a simple flowchart to determine eligibility for an S-ICD that can be easily implemented in daily clinical practice (Figure).

In recent years, studies have debated the impact of gender on the presentation and clinical course of HCM, with research showing that at time of myectomy, women are older, have worse diastolic function and more advanced cardiac remodeling. The clinical impact of these differences is unknown. We included 221 HCM patients (57% men) who underwent septal myectomy and are followed in our center. Time to treatment was calculated in relation to symptom onset. Pre- and post-operative clinical and echocardiographic data were collected. Gender differences were assessed at baseline and in survival analyses for the composite endpoint of all-cause mortality, cardiac transplantation, re-intervention and aborted sudden cardiac death. Women were older at time of myectomy, but time until treatment was similar (table). Pre-operative echocardiographic indices were comparable among groups, but were significantly higher in women when correcting for body surface area. At three months, no differences were found in clinical and echocardiographic results. After 6.1 [2.9–10.1] years, 24% of women and 23% of men had reached the composite endpoint (p=0.30, figure). Gender comparison pre- and post-myectomy Men (n=125) Women (n=96) p value Age 49±14 54±17 0.02 Maximal wall thickness, mm 19.9±4.7 19.8±5.8 0.97 Indexed maximal wall thickness, mm/m2 9.8±2.5 11.5±4.5 0.001 Left atrial diameter, mm 48.1±7.3 45.9±7.3 0.06 Indexed left atrial diameter, mm/m2 23.5±3.5 26.5±7.5 0.002 LV end-diastolic diameter, mm 45.4±7.6 42.8±5.6 0.04 Indexed LV end-diastolic diameter, mm/m2 22.1±3.7 23.6±3.0 0.02 Gradient reduction, %* 75.1±25.0 72.9±28.6 0.63 Improvement in symptoms*† 97 (95%) 64 (89%) 0.34 MWT = maximal wall thickness; LV = left ventricle. *At three months follow-up; †Defined as a reduction of ≥1 NYHA class, measured in 102 men and 72 women. Survival after myectomy Although women present later in life and seem to have more advanced disease at time of myectomy, time to treatment is similar and survival after myectomy is excellent for both men and women.

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.

Background Previous studies have reported that global longitudinal strain (GLS) is reduced in patients with hypertrophic cardiomyopathy (HCM) while left ventricular ejection fraction (LVEF) is normal. Our aim was to assess GLS in individuals with HCM mutations without hypertrophic changes and to determine its prognostic value for the development of HCM. Methods and results This retrospective case-control and cohort study included 120 HCM mutation carriers and 110 controls. GLS and LVEF were assessed with Tomtec Imaging software. Age, gender, and body surface area were similar in mutation carriers and controls. Compared to controls, mutation carriers had a higher maximal wall thickness (9 ± 2 vs 8 ± 2 mm, p

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

Dobutamine stress myocardial perfusion imaging (MPI) is a useful alternative for the evaluation of coronary artery disease (CAD) in elderly patients who are unable to perform an exercise stress test. However, data on the long-term prognostic value of stress MPI in elderly patients are lacking. Therefore, this study evaluated the long-term prognostic value of dobutamine stress MPI in elderly patients unable to perform an exercise test. The study population consisted of 247 elderly patients (mean age 71 ± 5 years) who underwent dobutamine stress single-photon emission computed tomography (SPECT) MPI. An abnormal SPECT study was defined as the presence of fixed and/or reversible perfusion defects. A summed stress score (SSS) was obtained to estimate the extent and severity of perfusion defects. End points during follow-up were all-cause mortality, cardiac mortality, and nonfatal myocardial infarction (MI). During a median follow-up of 14 years (range 12-16), 168 (68%) patients died (all-cause mortality), of which 56 (23%) were due to cardiac causes. Nonfatal MI occurred in 19 (8%) patients. Kaplan-Meier survival curves showed that MPI provided optimal risk stratification in patients with normal and abnormal MPI. Multivariable analysis identified an abnormal MPI as a strong significant predictor of all-cause mortality and cardiac events. A multivariable analysis also revealed that a reversible defect and SSS were strong long-term predictors of cardiac mortality and hard cardiac events. Dobutamine stress 99mTc-tetrofosmin SPECT provides incremental prognostic information for the prediction of long-term cardiovascular outcomes in elderly patients, unable to perform exercise testing. Dobutamine stress MPI is useful in risk classifying elderly patients.

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.

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.

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

Background Adverse left ventricular (LV) remodeling predicts heart failure symptoms and overt LV dysfunction in patients with hypertrophic cardiomyopathy (HCM), but its influence on the occurrence of sudden cardiac death (SCD) is unknown. The aim of this study was to investigate the effect of adverse LV remodeling on SCD risk in patients with HCM. Hypothesis Adverse LV remodeling increases SCD in HCM patients. Methods This study included 41 patients with HCM who experienced SCD; each case was matched with 3 controls based on age, gender, and time of first contact. In this population of 164 patients, predictors of SCD were identified using univariable and multivariable logistic regression and expressed as odds ratio (OR) with 95% confidence interval (CI). Results Baseline characteristics, such as New York Heart Association (NYHA) class, systolic and diastolic left ventricular function, left ventricular wall thickness, left atrial size, atrial fibrillation, and established risk factors for SCD were similar in cases and controls. Independent predictors of SCD during follow-up (median follow-up, 7.7 ± 6.5 years) were: increase in NYHA class (OR: 8.7 [95% CI: 2.5-30.5], P = 0.001), decrease of fractional shortening (per % decrease, OR: 1.09 [95% CI: 1.03-1.14], P = 0.001), and decrease of diastolic function (OR: 3.5 [95% CI: 1.2-10.2], P = 0.02). Conclusions This study shows that SCD risk in HCM increases when adverse remodeling occurs. Because cases and controls were similar at baseline, these findings emphasize the importance of vigilant follow-up of HCM patients and could aid clinical decision making concerning implantable cardioverter-defibrillator implantation, especially in patients with moderate risk for SCD.

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.

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.

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.

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.

The goal of this study was to evaluate the very long-term outcome after normal exercise 99mTc-sestamibi myocardial perfusion single-photon emission computed tomography (SPECT). Exercise 99mTc-sestamibi SPECT is widely used for risk stratification, but data on very long-term outcome after a normal test are scarce. A consecutive group of 233 patients (122 men, mean age 54 ± 12 years) with known or suspected coronary artery disease (CAD) underwent exercise 99mTc-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. 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. Patients with suspected or known CAD and normal exercise 99mTc-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.

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.

Aim To evaluate the agreement between contrast-enhanced ultrasound imaging and histopathology in an animal model of atherosclerosis. Methods and results Atherosclerosis was studied in both femoral arteries of four Rapacz familial hypercholesterolaemia (RFH) swine. Contrast-enhanced ultrasound imaging of the eight femoral arteries was performed at baseline and at 5, 12, 26, and 43 weeks follow-up after percutaneous transluminal stimulation of atherosclerosis to assess the progression of intima-media thickness (IMT) and the density and extent of the vasa vasorum network. Contrast-enhanced ultrasound imaging allowed an early detection of atherosclerosis and showed a significant gradual progression of atherosclerosis over time. IMT increased from 0.22 ± 0.05 mm at baseline to 0.45 ± 0.06 mm ( P < 0.001) at follow-up. The density of the vasa vasorum network increased during follow-up and was significantly higher in advanced than in early atherosclerosis. The findings with contrast-enhanced ultrasound were confirmed by histopathological specimens of the arterial wall. Conclusion Contrast-enhanced ultrasound is effective for in vivo detection of vasa vasorum in atherosclerotic plaques in the RFH swine model. After stimulation of atherosclerosis, contrast-enhanced ultrasound demonstrated a significantly increased IMT and significantly increased density of the vasa vasorum network in the developing atherosclerotic plaque, which was validated by histology.