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1.
Ultrasound Med Biol ; 46(5): 1071-1081, 2020 05.
Article in English | MEDLINE | ID: mdl-32115308

ABSTRACT

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.


Subject(s)
Contrast Media , Echocardiography/methods , Myocardial Perfusion Imaging/methods , Animals , Contrast Media/adverse effects , Echocardiography/adverse effects , Humans , Mechanical Thrombolysis/methods , Microbubbles , Myocardial Ischemia/diagnostic imaging , Myocardial Perfusion Imaging/adverse effects , Vasodilation
2.
Eur Heart J Qual Care Clin Outcomes ; 6(1): 10-18, 2020 01 01.
Article in English | MEDLINE | ID: mdl-31287501

ABSTRACT

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.


Subject(s)
Heart Valve Prosthesis Implantation/methods , Heart Valve Prosthesis , Tricuspid Valve Insufficiency/surgery , Tricuspid Valve/surgery , Ventricular Function/physiology , Humans , Risk Factors , Treatment Outcome , Tricuspid Valve Insufficiency/physiopathology
3.
Catheter Cardiovasc Interv ; 88(6): 945-952, 2016 Nov 15.
Article in English | MEDLINE | ID: mdl-26946355

ABSTRACT

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.


Subject(s)
Ablation Techniques/methods , Cardiomyopathy, Hypertrophic/therapy , Ethanol/administration & dosage , Heart Septum , Ventricular Outflow Obstruction/therapy , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnosis , Echocardiography , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective Studies , Time Factors , Treatment Outcome , Ventricular Outflow Obstruction/diagnosis , Ventricular Outflow Obstruction/etiology
4.
Circ Arrhythm Electrophysiol ; 8(4): 829-35, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25922410

ABSTRACT

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.


Subject(s)
Cardiology , Cardiomyopathy, Hypertrophic/complications , Death, Sudden, Cardiac/prevention & control , Practice Guidelines as Topic/standards , Primary Prevention/standards , Risk Assessment/methods , Societies, Medical , Adult , Aged , Cardiomyopathy, Hypertrophic/diagnosis , Death, Sudden, Cardiac/epidemiology , Death, Sudden, Cardiac/etiology , Europe/epidemiology , Female , Humans , Incidence , Male , Middle Aged , ROC Curve , Risk Factors , Survival Rate/trends
5.
Am J Cardiol ; 115(5): 670-5, 2015 Mar 01.
Article in English | MEDLINE | ID: mdl-25591899

ABSTRACT

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.


Subject(s)
Cardiomyopathy, Hypertrophic/mortality , Cardiomyopathy, Hypertrophic/surgery , Mitral Valve/surgery , Adult , Aged , Cardiomyopathy, Hypertrophic/complications , Cohort Studies , Female , Humans , Male , Middle Aged , Mitral Valve Insufficiency/complications , Mitral Valve Insufficiency/mortality , Mitral Valve Insufficiency/surgery , Survival Rate , Time Factors , Treatment Outcome
6.
JACC Heart Fail ; 2(6): 630-6, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25447346

ABSTRACT

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.


Subject(s)
Ablation Techniques/methods , Cardiomyopathy, Hypertrophic/therapy , Defibrillators, Implantable , Ethanol/therapeutic use , Solvents/therapeutic use , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/therapy , Cardiomyopathy, Hypertrophic/mortality , Chronic Disease , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Risk Factors , Treatment Outcome , Ventricular Outflow Obstruction/therapy
7.
Clin Cardiol ; 37(8): 493-8, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25044226

ABSTRACT

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.


Subject(s)
Cardiomyopathy, Hypertrophic/complications , Death, Sudden, Cardiac/etiology , Ventricular Dysfunction, Left/etiology , Ventricular Function, Left , Ventricular Remodeling , Adolescent , Adult , Aged , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/mortality , Cardiomyopathy, Hypertrophic/physiopathology , Case-Control Studies , Chi-Square Distribution , Death, Sudden, Cardiac/pathology , Female , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Odds Ratio , Risk Assessment , Risk Factors , Time Factors , Ventricular Dysfunction, Left/diagnosis , Ventricular Dysfunction, Left/physiopathology , Young Adult
8.
Pflugers Arch ; 466(8): 1619-33, 2014 Aug.
Article in English | MEDLINE | ID: mdl-24186209

ABSTRACT

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.


Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Carrier Proteins/genetics , Mutation , Myocytes, Cardiac/physiology , Adult , Aged , Female , Humans , Kinetics , Male , Middle Aged , Myocardial Contraction/physiology , Young Adult
9.
J Mol Cell Cardiol ; 65: 59-66, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24083979

ABSTRACT

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.


Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Carrier Proteins/genetics , Gene Expression Profiling , MicroRNAs/genetics , Mutation/genetics , Myocardium/metabolism , Transcriptome/genetics , Adult , Aged , Cardiomyopathy, Hypertrophic/pathology , Computer Simulation , Female , Genome, Human/genetics , Humans , Male , MicroRNAs/metabolism , Middle Aged , Myocardium/pathology , Phosphorylation , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , TRPM Cation Channels/genetics , TRPM Cation Channels/metabolism , Troponin I/metabolism , Young Adult
10.
Am Heart J ; 166(3): 496-502, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24016499

ABSTRACT

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.


Subject(s)
Cardiac Resynchronization Therapy/statistics & numerical data , Cardiomyopathy, Hypertrophic/therapy , Death, Sudden, Cardiac/etiology , Defibrillators, Implantable/adverse effects , Adult , Cardiomyopathy, Hypertrophic/mortality , Death, Sudden, Cardiac/prevention & control , Female , Follow-Up Studies , Humans , Male , Middle Aged , Regression Analysis , Risk Assessment , Risk Factors , Treatment Outcome
11.
Cardiovasc Res ; 99(3): 432-41, 2013 Aug 01.
Article in English | MEDLINE | ID: mdl-23674513

ABSTRACT

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.


Subject(s)
Cardiac Myosins/genetics , Cardiac Myosins/physiology , Cardiomyopathy, Hypertrophic, Familial/genetics , Cardiomyopathy, Hypertrophic, Familial/physiopathology , Mutation , Myocardial Contraction/genetics , Myosin Heavy Chains/genetics , Myosin Heavy Chains/physiology , Adult , Aged , Calcium/metabolism , Cardiomyopathy, Hypertrophic, Familial/pathology , Cell Enlargement , Female , Fibrosis , Humans , Male , Middle Aged , Myocytes, Cardiac/pathology , Myocytes, Cardiac/physiology , Myofibrils/pathology , Sarcomeres/pathology , Sarcomeres/physiology , Young Adult
12.
Circ Res ; 112(11): 1491-505, 2013 May 24.
Article in English | MEDLINE | ID: mdl-23508784

ABSTRACT

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.


Subject(s)
Cardiomyopathy, Hypertrophic/genetics , Cardiomyopathy, Hypertrophic/pathology , Myofibrils/pathology , Myofibrils/physiology , Sarcomeres/pathology , Sarcomeres/physiology , Adolescent , Adult , Aged , Animals , Calcium/metabolism , Cardiac Myosins/genetics , Cardiomyopathy, Hypertrophic/physiopathology , Carrier Proteins/genetics , Cyclic AMP-Dependent Protein Kinases/metabolism , Female , Humans , Isometric Contraction/physiology , MAP Kinase Kinase Kinases/genetics , Male , Mice , Middle Aged , Mutation, Missense , Myocardial Contraction/physiology , Myocardium/metabolism , Myocardium/pathology , Myosin Heavy Chains/genetics , Phosphorylation/physiology , Protein Serine-Threonine Kinases , Tropomyosin/genetics , Troponin T/genetics , Young Adult
13.
Echocardiography ; 30(3): 293-300, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23347129

ABSTRACT

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.


Subject(s)
Aortic Valve Stenosis/diagnostic imaging , Aortic Valve Stenosis/physiopathology , Elasticity Imaging Techniques/methods , Heart Atria/diagnostic imaging , Heart Atria/physiopathology , Ventricular Dysfunction, Left/diagnostic imaging , Ventricular Dysfunction, Left/physiopathology , Aged , Aortic Valve Stenosis/complications , Echocardiography/methods , Elastic Modulus , Female , Humans , Male , Middle Aged , Reproducibility of Results , Sensitivity and Specificity , Ventricular Dysfunction, Left/etiology
14.
Eur Heart J Cardiovasc Imaging ; 14(1): 56-61, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22645206

ABSTRACT

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.


Subject(s)
Atherosclerosis/diagnostic imaging , Carotid Arteries/diagnostic imaging , Carotid Intima-Media Thickness , Carotid Stenosis/diagnostic imaging , Contrast Media , Echocardiography, Doppler, Color/methods , Aged , Atherosclerosis/diagnosis , Carotid Stenosis/complications , Female , Humans , Male , Middle Aged , Outpatients , Plaque, Atherosclerotic/diagnostic imaging , Predictive Value of Tests , Prospective Studies , Risk Assessment , Risk Factors , Sensitivity and Specificity
15.
Eur Heart J Cardiovasc Imaging ; 14(5): 435-42, 2013 May.
Article in English | MEDLINE | ID: mdl-22898715

ABSTRACT

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.


Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Echocardiography, Doppler/methods , Heart Septum/diagnostic imaging , Heart Ventricles/diagnostic imaging , Image Interpretation, Computer-Assisted , Adult , Analysis of Variance , Cardiomyopathy, Hypertrophic/physiopathology , Case-Control Studies , Female , Follow-Up Studies , Heart Septum/physiopathology , Heart Ventricles/physiopathology , Humans , Male , Middle Aged , Monitoring, Physiologic/methods , Observer Variation , Reference Values , Rotation
16.
Echocardiography ; 30(5): 558-63, 2013 May.
Article in English | MEDLINE | ID: mdl-23228071

ABSTRACT

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.


Subject(s)
Cardiomyopathy, Hypertrophic/diagnostic imaging , Cardiomyopathy, Hypertrophic/genetics , Heterozygote , Ventricular Dysfunction, Left/diagnostic imaging , Adult , Case-Control Studies , Diastole/physiology , Echocardiography, Doppler, Pulsed/methods , Female , Humans , Male , Middle Aged , Mitral Valve/diagnostic imaging , Mitral Valve/physiopathology , Pedigree , Phenotype , Prospective Studies , Reference Values , Risk Assessment , Systole/physiology , Ventricular Dysfunction, Left/genetics , Ventricular Dysfunction, Right/diagnostic imaging , Ventricular Dysfunction, Right/genetics
17.
J Am Soc Echocardiogr ; 26(3): 261-9, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23228655

ABSTRACT

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.


Subject(s)
Echocardiography, Three-Dimensional , Mitral Valve Insufficiency/diagnostic imaging , Mitral Valve Insufficiency/physiopathology , Aged , Blood Flow Velocity , Female , Humans , Male , Middle Aged , Severity of Illness Index , Statistics, Nonparametric
18.
Circ Heart Fail ; 5(5): 552-9, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22821634

ABSTRACT

BACKGROUND: Previous observational studies demonstrated that patients with hypertrophic cardiomyopathy at risk for sudden cardiac death (SCD) may benefit from implantable cardioverter defibrillator (ICD) therapy. A complete overview of outcome and complications after ICD therapy is currently not available. This study pools data from published studies on outcome and complications after ICD therapy in patients with hypertrophic cardiomyopathy. METHODS AND RESULTS: A PubMed database search returned 27 studies on 16 cohorts reporting outcome and complications after ICD therapy in patients with hypertrophic cardiomyopathy. In case of >1 publications on a particular cohort, the publication with the largest number of patients was included in the meta-analysis. ICD interventions, complications, and mortality rates were extracted, pooled, and analyzed. There were 2190 patients (mean age, 42 years; 38% women), most of whom (83%) received an ICD for primary prevention of SCD. Risk factors for SCD were left ventricular wall thickness ≥30 mm (20%), family history of SCD (43%), nonsustained ventricular tachycardia (46%), syncope (41%), and abnormal blood pressure response (25%). During the 3.7-year follow-up, the annualized cardiac mortality rate was 0.6%, the noncardiac mortality rate was 0.4%, and the appropriate ICD intervention rate was 3.3%. The annualized inappropriate ICD intervention rate was 4.8% and the annualized ICD-related complication rate was 3.4%. CONCLUSIONS: This meta-analysis demonstrates a low cardiac and noncardiac mortality rate after ICD therapy in patients with hypertrophic cardiomyopathy. Appropriate ICD intervention occurred at a rate of 3.3%/year, thereby, most probably, preventing SCD. Inappropriate ICD intervention and complications are not uncommon.


Subject(s)
Cardiomyopathy, Hypertrophic/therapy , Death, Sudden, Cardiac/prevention & control , Defibrillators, Implantable , Electric Countershock/instrumentation , Adolescent , Adult , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/mortality , Cause of Death , Death, Sudden, Cardiac/etiology , Defibrillators, Implantable/adverse effects , Electric Countershock/adverse effects , Electric Countershock/mortality , Female , Humans , Male , Middle Aged , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , Young Adult
19.
Eur J Hum Genet ; 20(10): 1071-7, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22569109

ABSTRACT

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.


Subject(s)
Cardiomyopathy, Hypertrophic, Familial/genetics , Carrier Proteins/genetics , Phenotype , Polymorphism, Single Nucleotide , Renin-Angiotensin System/genetics , Adult , Female , Genetic Association Studies , Genetic Loci , Heterozygote , Humans , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/genetics , Male , Pedigree , Ultrasonography , Ventricular Septum/diagnostic imaging
20.
Ultrasound Med Biol ; 38(4): 593-600, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22341054

ABSTRACT

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


Subject(s)
Carotid Arteries/diagnostic imaging , Image Enhancement/methods , Artifacts , Contrast Media , Female , Humans , In Vitro Techniques , Male , Middle Aged , Phantoms, Imaging , Phospholipids , Sulfur Hexafluoride , Ultrasonography
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