New Applications in Echocardiography for Ultrasound Contrast Agents in the 21st Century.

Contrast echocardiography microbubbles are ultrasound-enhancing agents that were originally designed to help improve endocardial border definition, known as left ventricle opacification, and to enhance Doppler signals. Over time, contrast microbubbles are used to assess myocardial perfusion because they travel through the capillaries of the cardiac circulation. Current research provides good evidence that myocardial perfusion echocardiography improves comprehensive echocardiographic evaluations of ischemic heart disease. The approval of regulatory authorities and the availability of quantitative operator-independent analysis software will hopefully prompt physicians and sonographers to implement myocardial perfusion echocardiography into the daily workflow of echo laboratories. New diagnostic and therapeutic applications will result in improved patient care, especially in the area of sonothrombolysis, where preliminary data have already shown utilization in ST elevation myocardial infarction, improving left ventricular systolic function and reducing the need for implantable defibrillators at 6-mo follow-up. This review gives an overview of the applications of myocardial perfusion imaging with ultrasound. Each cited study had institutional review board/institutional animal care and use approval.

Outcomes after surgery for functional tricuspid regurgitation: a systematic review and meta-analysis.

AIMS: This study aims to provide a contemporary overview of outcomes after tricuspid valve (TV) surgery for functional tricuspid regurgitation (TR). METHODS AND RESULTS: The literature was systematically searched for papers published between January 2005 and December 2017 reporting on clinical/echocardiographic outcomes after TV surgery for functional TR. A random effects meta-analysis was conducted for outcome variables, and late outcomes are visualized by pooled Kaplan-Meier curves. Subgroup analyses were performed for studies with a within-study comparison of suture vs. ring repair and flexible vs. rigid ring repair. Eighty-seven publications were included, encompassing 13 184 patients (mean age: 62.1 ± 11.8 years, 55% females). A mitral valve procedure was performed in 92% of patients. Pooled mean follow-up was 4.0 ± 2.8 years. Pooled early mortality was 3.9% (95% CI: 3.2-4.6), and late mortality rate was 2.7%/year (95% CI: 2.0-3.5), of which approximately half was cardiac-related 1.2%/year (95% CI: 0.8-1.9). Pooled risk of early moderate-to-severe TR at discharge was 9.4% (95% CI: 7.0-12.1). Late moderate-to-severe TR rate after discharge was 1.9%/year (95% CI: 1.0-3.5). Late reintervention rate was 0.3%/year (95% CI: 0.2-0.4). Mortality and overall (early and late) TR rate were comparable between suture vs. ring annuloplasty (14 studies), whereas overall TR rate was higher after flexible ring vs. rigid ring annuloplasty (6 studies) (7.5%/year vs. 3.9%/year, P = 0.002). CONCLUSION: This study shows that patients undergoing surgery for functional tricuspid regurgitation (FTR) have an acceptable early and late mortality. However, TR remains prevalent after surgery. The results of this study can be used to inform patients and clinicians about the expected outcome after surgery for FTR and can results serve as a benchmark for the performance of emerging transcatheter TV interventions.

Effect of alcohol dosage on long-term outcomes after alcohol septal ablation in patients with hypertrophic cardiomyopathy.

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

Validation of the 2014 European Society of Cardiology guidelines risk prediction model for the primary prevention of sudden cardiac death in hypertrophic cardiomyopathy.

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.

Long-term benefit of myectomy and anterior mitral leaflet extension in obstructive hypertrophic cardiomyopathy.

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

Long-term outcomes after medical and invasive treatment in patients with hypertrophic cardiomyopathy.

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

Impact of adverse left ventricular remodeling on sudden cardiac death in patients with hypertrophic cardiomyopathy.

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.

Preserved cross-bridge kinetics in human hypertrophic cardiomyopathy patients with MYBPC3 mutations.

Mutations in the MYBPC3 gene, encoding cardiac myosin binding protein C (cMyBP-C) are frequent causes of hypertrophic cardiomyopathy (HCM). Previously, we have presented evidence for reduced cMyBP-C expression (haploinsufficiency), in patients with a truncation mutation in MYBPC3. In mice, lacking cMyBP-C cross-bridge kinetics was accelerated. In this study, we investigated whether cross-bridge kinetics was altered in myectomy samples from HCM patients harboring heterozygous MYBPC3 mutations (MYBPC3mut). Isometric force and the rate of force redevelopment (k tr) at different activating Ca(2+) concentrations were measured in mechanically isolated Triton-permeabilized cardiomyocytes from MYBPC3mut (n = 18) and donor (n = 7) tissue. Furthermore, the stretch activation response of cardiomyocytes was measured in tissue from eight MYBPC3mut patients and five donors to assess the rate of initial force relaxation (k 1) and the rate and magnitude of the transient increase in force (k 2 and P 3, respectively) after a rapid stretch. Maximal force development of the cardiomyocytes was reduced in MYBPC3mut (24.5 ± 2.3 kN/m(2)) compared to donor (34.9 ± 1.6 kN/m(2)). The rates of force redevelopment in MYBPC3mut and donor over a range of Ca(2+) concentrations were similar (k tr at maximal activation: 0.63 ± 0.03 and 0.75 ± 0.09 s(-1), respectively). Moreover, the stretch activation parameters did not differ significantly between MYBPC3mut and donor (k 1: 8.5±0.5 and 8.8 ± 0.4 s(-1); k 2: 0.77 ± 0.06 and 0.74 ± 0.09 s(-1); P 3: 0.08 ± 0.01 and 0.09 ± 0.01, respectively). Incubation with protein kinase A accelerated k 1 in MYBPC3mut and donor to a similar extent. Our experiments indicate that, at the cMyBP-C expression levels in this patient group (63 ± 6 % relative to donors), cross-bridge kinetics are preserved and that the depressed maximal force development is not explained by perturbation of cross-bridge kinetics.

Cardiac dysfunction after aneurysmal subarachnoid hemorrhage: relationship with outcome.

OBJECTIVE: To assess whether cardiac abnormalities after aneurysmal subarachnoid hemorrhage (aSAH) are associated with delayed cerebral ischemia (DCI) and clinical outcome, independent from known clinical risk factors for these outcomes. METHODS: In a prospective, multicenter cohort study, we performed echocardiography and ECG and measured biochemical markers for myocardial damage in patients with aSAH. Outcomes were DCI, death, and poor clinical outcome (death or dependency for activities of daily living) at 3 months. With multivariable Poisson regression analysis, we calculated risk ratios (RRs) with corresponding 95% confidence intervals. We used survival analysis to assess cumulative percentage of death in patients with and without echocardiographic wall motion abnormalities (WMAs). RESULTS: We included 301 patients with a mean age of 57 years; 70% were women. A wall motion score index ≥1.2 had an adjusted RR of 1.2 (0.9-1.6) for DCI, 1.9 (1.1-3.3) for death, and 1.8 (1.1-3.0) for poor outcome. Midventricular WMAs had adjusted RRs of 1.1 (0.8-1.4) for DCI, 2.3 (1.4-3.8) for death, and 2.2 (1.4-3.5) for poor outcome. For apical WMAs, adjusted RRs were 1.3 (1.1-1.7) for DCI, 1.5 (0.8-2.7) for death, and 1.4 (0.8-2.5) for poor outcome. Elevated troponin T levels, ST-segment changes, and low voltage on the admission ECGs had a univariable association with death but were not independent predictors for outcome. CONCLUSION: WMAs are independent risk factors for clinical outcome after aSAH. This relation is partly explained by a higher risk of DCI. Further study should aim at treatment strategies for these aSAH-related cardiac abnormalities to improve clinical outcome.

MicroRNA transcriptome profiling in cardiac tissue of hypertrophic cardiomyopathy patients with MYBPC3 mutations.

Hypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in genes encoding sarcomeric proteins. One of the most frequent affected genes is MYBPC3, which encodes the thick filament protein cardiac myosin binding protein C. Despite the prevalence of HCM, disease pathology and clinical outcome of sarcomeric mutations are largely unknown. We hypothesized that microRNAs (miRNAs) could play a role in the disease process. To determine which miRNAs were changed in expression, miRNA arrays were performed on heart tissue from HCM patients with a MYBPC3 mutation (n=6) and compared with hearts of non-failing donors (n=6). 532 out of 664 analyzed miRNAs were expressed in at least one heart sample. 13 miRNAs were differentially expressed in HCM compared with donors (at p<0.01, fold change ≥ 2). The genomic context of these differentially expressed miRNAs revealed that miR-204 (fold change 2.4 in HCM vs. donor) was located in an intron of the TRPM3 gene, encoding an aspecific cation channel involved in calcium entry. RT-PCR analysis revealed a trend towards TRPM3 upregulation in HCM compared with donor myocardium (fold change 2.3, p=0.078). In silico identification of mRNA targets of differentially expressed miRNAs showed a large proportion of genes involved in cardiac hypertrophy and cardiac beta-adrenergic receptor signaling and we showed reduced phosphorylation of cardiac troponin I in the HCM myocardium when compared with donor. HCM patients with MYBPC3 mutations have a specific miRNA expression profile. Downstream mRNA targets reveal possible involvement in cardiac signaling pathways.

Implantable cardioverter-defibrillators in hypertrophic cardiomyopathy: patient outcomes, rate of appropriate and inappropriate interventions, and complications.

BACKGROUND: Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM), but this can be prevented by an implantable cardioverter-defibrillator (ICD). The aim of this study is to evaluate HCM patients with ICDs for primary or secondary prevention of SCD. METHODS: The study population consisted of all HCM patients with an ICD in 2 tertiary referral clinics. End points during follow-up were total and cardiac mortality, appropriate and inappropriate ICD intervention, and device-related complications. Cox-regression analysis was performed to identify predictors of outcome. RESULTS: ICDs were implanted in 134 patients with HCM (mean age 44 ± 17 years, 34% women, 4.2 ± 4.8 years follow-up). Annualized cardiac mortality rate was 3.4% per year and associated with New York Heart Association class III or IV (HR 5.2 [2.0-14, P = .002]) and cardiac resynchronization therapy (HR 6.3 [2.1-20, P = .02]). Appropriate ICD interventions occurred in 38 patients (6.8%/year) and was associated with implantation for secondary prevention of SCD (HR 4.0 [1.8-9.1], P = .001) and male gender (HR 3.3 [1.2-9.0], P = .02). Inappropriate ICD intervention occurred in 21 patients (3.7%/year) and in 20 patients device related complications were documented (3.6%/year). CONCLUSION: ICDs successfully abort life-threatening arrhythmias in HCM patients at increased risk of SCD with an annualized intervention rate of 6.8% per year. End-stage heart failure is the main cause of mortality in these patients. The annualized rate of inappropriate ICD intervention was 3.7% per year, whereas device-related complications occurred 3.6% per year.

Comparison of sulfur hexafluoride microbubble (SonoVue)-enhanced myocardial contrast echocardiography with gated single-photon emission computed tomography for detection of significant coronary artery disease: a large European multicenter study.

OBJECTIVES: The purpose of this study was to compare sulfur hexafluoride microbubble (SonoVue)-enhanced myocardial contrast echocardiography (MCE) with single-photon emission computed tomography (SPECT) relative to coronary angiography (CA) for assessment of coronary artery disease (CAD). BACKGROUND: Small-scale studies have shown that myocardial perfusion assessed by SonoVue-enhanced MCE is a viable alternative to SPECT for CAD assessment. However, large multicenter studies are lacking. METHODS: Patients referred for myocardial ischemia testing at 34 centers underwent rest/vasodilator SonoVue-enhanced flash-replenishment MCE, standard (99m)Tc-labeled electrocardiography-gated SPECT, and quantitative CA within 1 month. Myocardial ischemia assessments by 3 independent, blinded readers for MCE and 3 readers for SPECT were collapsed into 1 diagnosis per patient per technique and were compared to CA (reference standard) read by 1 independent blinded reader. RESULTS: Of 628 enrolled patients who received SonoVue (71% males; mean age: 64 years; >1 cardiovascular [CV] risk factor in 99% of patients) 516 patients underwent all 3 examinations, of whom 161 (31.2%) had ≥70% stenosis (131 had single-vessel disease [SVD]; 30 had multivessel disease), and 310 (60.1%) had ≥50% stenosis. Higher sensitivity was obtained with MCE than with SPECT (75.2% vs. 49.1%, respectively; p < 0.0001), although specificity was lower (52.4% vs. 80.6%, respectively; p < 0.0001) for ≥70% stenosis. Similar findings were obtained for patients with ≥50% stenosis. Sensitivity levels for detection of SVD and proximal disease for ≥70% stenosis were higher for MCE (72.5% vs. 42.7%, respectively; p < 0.0001; 80% vs. 58%, respectively; p = 0.005, respectively). CONCLUSIONS: SonoVue-enhanced MCE demonstrated superior sensitivity but lower specificity for detection of CAD compared to SPECT in a population with a high incidence of CV risk factors and intermediate-high prevalence of CAD. (A phase III study to compare SonoVue® enhanced myocardial echocardiography [MCE] to single photon emission computerized tomography [ECG-GATED SPECT], at rest and at peak of low-dose Dipyridamole stress test, in the assessment of significant coronary artery disease [CAD] in patients with suspect or known CAD using Coronary Angiography as Gold Standard-SonoVue MCE vs SPECT; EUCTR2007-003492-39-GR).

Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy.

AIMS: Familial hypertrophic cardiomyopathy (HCM), frequently caused by sarcomeric gene mutations, is characterized by cellular dysfunction and asymmetric left-ventricular (LV) hypertrophy. We studied whether cellular dysfunction is due to an intrinsic sarcomere defect or cardiomyocyte remodelling. METHODS AND RESULTS: Cardiac samples from 43 sarcomere mutation-positive patients (HCMmut: mutations in thick (MYBPC3, MYH7) and thin (TPM1, TNNI3, TNNT2) myofilament genes) were compared with 14 sarcomere mutation-negative patients (HCMsmn), eight patients with secondary LV hypertrophy due to aortic stenosis (LVHao) and 13 donors. Force measurements in single membrane-permeabilized cardiomyocytes revealed significantly lower maximal force generating capacity (Fmax) in HCMmut (21 ± 1 kN/m²) and HCMsmn (26 ± 3 kN/m²) compared with donor (36 ± 2 kN/m²). Cardiomyocyte remodelling was more severe in HCMmut compared with HCMsmn based on significantly lower myofibril density (49 ± 2 vs. 63 ± 5%) and significantly higher cardiomyocyte area (915 ± 15 vs. 612 ± 11 µm²). Low Fmax in MYBPC3mut, TNNI3mut, HCMsmn, and LVHao was normalized to donor values after correction for myofibril density. However, Fmax was significantly lower in MYH7mut, TPM1mut, and TNNT2mut even after correction for myofibril density. In accordance, measurements in single myofibrils showed very low Fmax in MYH7mut, TPM1mut, and TNNT2mut compared with donor (respectively, 73 ± 3, 70 ± 7, 83 ± 6, and 113 ± 5 kN/m²). In addition, force was lower in MYH7mut cardiomyocytes compared with MYBPC3mut, HCMsmn, and donor at submaximal [Ca²âº]. CONCLUSION: Low cardiomyocyte Fmax in HCM patients is largely explained by hypertrophy and reduced myofibril density. MYH7 mutations reduce force generating capacity of sarcomeres at maximal and submaximal [Ca²âº]. These hypocontractile sarcomeres may represent the primary abnormality in patients with MYH7 mutations.

Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.

RATIONALE: High-myofilament Ca(2+) sensitivity has been proposed as a trigger of disease pathogenesis in familial hypertrophic cardiomyopathy (HCM) on the basis of in vitro and transgenic mice studies. However, myofilament Ca(2+) sensitivity depends on protein phosphorylation and muscle length, and at present, data in humans are scarce. OBJECTIVE: To investigate whether high myofilament Ca(2+) sensitivity and perturbed length-dependent activation are characteristics for human HCM with mutations in thick and thin filament proteins. METHODS AND RESULTS: Cardiac samples from patients with HCM harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM and nonfailing donors. Cardiomyocyte force measurements showed higher myofilament Ca(2+) sensitivity in all HCM samples and low phosphorylation of protein kinase A (PKA) targets compared with donors. After exogenous PKA treatment, myofilament Ca(2+) sensitivity was similar (MYBPC3mut, TPM1mut, sarcomere mutation-negative HCM), higher (MYH7mut, TNNT2mut), or even significantly lower (TNNI3mut) compared with donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in sarcomere mutation-negative HCM and HCM with truncating MYBPC3 mutations but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values. CONCLUSIONS: High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via posttranslational modifications other than PKA hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.

Assessment of subendocardial contractile function in aortic stenosis: a study using speckle tracking echocardiography.

BACKGROUND: Angina and an electrocardiographic strain pattern are potential manifestations of subendocardial ischemia in aortic stenosis (AS). Left ventricular (LV) twist is known to increase proportionally to the severity of AS, which may be a result of loss of the inhibiting effect of the subendocardial fibers due to subendocardial dysfunction. It has also been shown that the ratio of LV twist to circumferential shortening of the endocardium (twist-to-shortening ratio [TSR]) is a reliable parameter of subendocardial dysfunction. The aim of this study was to investigate whether these markers are increased in AS patients with angina and/or electrocardiographic strain. METHODS: The study comprised 60 AS patients with an aortic valve area <2.0 cm(2) and LV ejection fraction >50%, and 30 healthy-for age and gender matched-control subjects. LV rotation parameters were determined by speckle tracking echocardiography. RESULTS: Comparison of patients without angina and strain (n = 22), with either angina or strain (n = 28), and with both angina and strain (n = 8), showed highest peak systolic LV apical rotation, peak systolic LV twist, and TSR, in patients with more signs of subendocardial ischemia. In a multivariate linear regression model, only severity of AS and the presence of angina and/or strain could be identified as independent predictors of peak systolic LV twist and TSR. CONCLUSIONS: Peak systolic LV twist and TSR are increased in AS patients and related to the severity of AS and symptoms (angina) or electrocardiographic signs (strain) compatible with subendocardial ischemia.

Assessment of subclinical atherosclerosis using contrast-enhanced ultrasound.

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.

Regional left ventricular rotation and back-rotation in patients with reverse septal curvature hypertrophic cardiomyopathy.

AIMS: This study sought to investigate regional left ventricular (LV) rotation in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: The study comprised 44 patients with HCM with a typical reverse septal curvature (age 40 ± 14 years, 33 men) and 44 healthy volunteers (age 39 ± 14 years, 32 men) in whom LV rotation could be assessed at the basal and apical LV level with speckle-tracking echocardiography, using the QLAB Advanced Quantification Software version 6.0 (Philips, Best, The Netherlands). In HCM patients, lower values of initial counter-clockwise rotation at the basal LV level (1.5 ± 1.2 vs. 0.6 ± 0.9°, P < 0.001) were seen, in particular in the septal segment (1.7 ± 1.6 vs. 0.4 ± 0.7°, P < 0.001). After this period, the direction of rotation changed to clockwise with a peak basal rotation of -4.8 ± 2.0° in controls vs. -6.1 ± 2.5° in HCM patients (P < 0.05). Peak basal rotation in HCM patients was in particular higher in the anterior (-6.6 ± 3.0 vs. -4.4 ± 2.4°, P < 0.01) and septal (-5.4 ± 2.6 vs. -3.9 ± 1.9°, P < 0.05) segments. The normalized (corrected for peak basal rotation) global back-rotation rate was lower in HCM patients (4.1 ± 3.1 vs. 6.3 ± 4.9 s(-1), P < 0.05), in particular driven by a lower rate in the septal segment (3.8 ± 2.6 vs. 6.4 ± 4.8 s(-1), P < 0.01). At the apical level, changes in rotation and back-rotation were more homogeneous. CONCLUSION: Changes in rotation and back-rotation at the LV basal level in HCM patients are mainly caused by regional changes in the basal septal and anterior segments, the segments mostly involved in the hypertrophic process.

Diastolic abnormalities in normal phenotype hypertrophic cardiomyopathy gene carriers: a study using speckle tracking echocardiography.

BACKGROUND: Tissue Doppler imaging (TDI) of the mitral annulus has been proposed as an alternative for the identification of hypertrophic cardiomyopathy (HCM) genetically affected subjects without left ventricular hypertrophy (G+/LVH-). Unfortunately, conflicting results have been described in the literature, potentially caused by the angle-dependency of TDI. This study sought to assess abnormalities in mitral annular velocities in G+/LVH- subjects as detected by speckle tracking echocardiography (STE). METHODS: The study population consisted of 23 consecutive genotyped family members without major or minor criteria for the diagnosis of HCM (mean age 37 ± 13 years, 9 men) and 23 healthy volunteers (age 38 ± 12 years, 12 men) who prospectively underwent STE. RESULTS: There were no significant differences in global peak systolic annular velocity (7.4 ± 1.2 vs. 7.1 ± 1.0 cm/sec) and early diastolic annular velocity (10.2 ± 2.5 vs. 11.3 ± 2.2 cm/sec) between G+/LVH- and control subjects. Global peak late diastolic annular velocity was higher in G+/LVH- subjects (8.1 ± 1.7 vs. 5.7 ± 1.1 cm/sec, P < 0.001). Regionally, this difference was seen in all 6 studied LV walls. CONCLUSIONS: This STE study confirms our previous TDI observations on increased peak late diastolic annular velocities in G+/LVH- subjects. Because of the complete overlap in early diastolic annular velocities this parameter cannot be used in the genotypes we studied to differentiate genotype (+) from genotype (-) individuals.

Geometric errors of the pulsed-wave Doppler flow method in quantifying degenerative mitral valve regurgitation: a three-dimensional echocardiography study.

BACKGROUND: The aim of this study was to estimate geometric errors made by the two-dimensional (2D) transthoracic echocardiographic (TTE) pulsed-wave Doppler flow (PWDF) method in calculating regurgitant volume (RVol) and effective regurgitant orifice area (EROA) in degenerative mitral regurgitation (MR) by comparison with the three-dimensional (3D) transesophageal echocardiographic (TEE) PWDF method. METHODS: RVol and EROA were calculated in 22 patients with degenerative MR using the conventional 2D TTE PWDF method on the basis of monoplanar dimensions and a circular geometric assumption of the cross-sectional areas (CSAs) of the mitral annulus (MA) and the left ventricular outflow tract (LVOT) and the 3D TEE PWDF method, in which the CSAs of the MA and LVOT were measured directly in "en face" views. Diameters of the MA and LVOT were also measured in similar views as with TTE imaging in 3D TEE data sets. RESULTS: Both the MA and LVOT were oval. Mean MA diameters were 41 ± 4 mm (3D TEE major axis), 31 ± 4 mm (3D TEE minor axis), 39 ± 5 mm (2D TTE imaging), and 38 ± 5 mm (2D TEE imaging). Mean LVOT diameters were 29 ± 4 mm (3D TEE major axis), 21 ± 2 mm (3D TEE minor axis), 22 ± 2 mm (2D TTE imaging), and 23 ± 2 mm (2D TEE imaging). Compared with 3D TEE measurements, mitral annular CSA was overestimated by 13 ± 12% on 2D TTE imaging and by 7 ± 14% on 2D TEE imaging, while LVOT CSA was underestimated by 23 ± 10% and 17 ± 10%, respectively. Mean values of RVol were 95 ± 43 mL (3D TEE PWDF), 137 ± 56 mL (2D TTE PWDF), 120 ± 45 mL (2D TEE PWDF), and 111 ± 49 mL (flow convergence). Mean EROAs were 69 ± 34 mm2 (3D TEE PWDF), 98 ± 45 mm2 (2D TTE PWDF), 88 ± 42 mm2 (2D TEE PWDF), and 79 ± 36 mm2 (flow convergence). Observer variability for 3D TEE imaging was better than for 2D imaging. CONCLUSIONS: The 2D TTE PWDF method overestimates mitral RVol and EROA significantly because monoplanar 2D measurements represent mitral annular major-axis diameter and LVOT minor-axis diameter, and assumed circular CSAs of the MA and LVOT are oval.