RESUMO
Contrast-enhanced ultrasound imaging is a radiation-free clinical diagnostic tool that uses biocompatible contrast agents to enhance ultrasound signal, in order to improve image clarity and diagnostic performance. Ultrasound enhancing agents (UEA), which are usually gas microbubbles, are administered intravenously either by bolus injection or continuous infusion. UEA increase the accuracy and reliability of echocardiography, leading to changes in treatment, improving patient outcomes and lowering overall health care costs. In this review we describe: (1) the current clinical applications of ultrasound enhancing agents in echocardiography, with a brief review of the evidence underlying each of these applications; (2) emerging diagnostic and therapeutic applications of microbubble enhanced echocardiography (MEE), which rely either on the specific properties and composition of ultrasound enhancing agents or on the technical advances of clinical ultrasound systems; and (3) safety of MEE.
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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.
Assuntos
Técnicas de Ablação/métodos , Cardiomiopatia Hipertrófica/terapia , Etanol/administração & dosagem , Septos Cardíacos , Obstrução do Fluxo Ventricular Externo/terapia , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Ecocardiografia , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Obstrução do Fluxo Ventricular Externo/diagnóstico , Obstrução do Fluxo Ventricular Externo/etiologiaRESUMO
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.
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Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/patologia , Miofibrilas/patologia , Miofibrilas/fisiologia , Sarcômeros/patologia , Sarcômeros/fisiologia , Adolescente , Adulto , Idoso , Animais , Cálcio/metabolismo , Miosinas Cardíacas/genética , Cardiomiopatia Hipertrófica/fisiopatologia , Proteínas de Transporte/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Feminino , Humanos , Contração Isométrica/fisiologia , MAP Quinase Quinase Quinases/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Miocárdio/patologia , Cadeias Pesadas de Miosina/genética , Fosforilação/fisiologia , Proteínas Serina-Treonina Quinases , Tropomiosina/genética , Troponina T/genética , Adulto JovemRESUMO
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.
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Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Mutação , Miócitos Cardíacos/fisiologia , Adulto , Idoso , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Adulto JovemRESUMO
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.
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Cardiomiopatia Hipertrófica/genética , Proteínas de Transporte/genética , Perfilação da Expressão Gênica , MicroRNAs/genética , Mutação/genética , Miocárdio/metabolismo , Transcriptoma/genética , Adulto , Idoso , Cardiomiopatia Hipertrófica/patologia , Simulação por Computador , Feminino , Genoma Humano/genética , Humanos , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Miocárdio/patologia , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Troponina I/metabolismo , Adulto JovemRESUMO
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.
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Terapia de Ressincronização Cardíaca/estatística & dados numéricos , Cardiomiopatia Hipertrófica/terapia , Morte Súbita Cardíaca/etiologia , Desfibriladores Implantáveis/efeitos adversos , Adulto , Cardiomiopatia Hipertrófica/mortalidade , Morte Súbita Cardíaca/prevenção & controle , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
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.
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Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/fisiopatologia , Técnicas de Imagem por Elasticidade/métodos , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/fisiopatologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia , Idoso , Estenose da Valva Aórtica/complicações , Ecocardiografia/métodos , Módulo de Elasticidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Disfunção Ventricular Esquerda/etiologiaRESUMO
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.
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Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/genética , Heterozigoto , Disfunção Ventricular Esquerda/diagnóstico por imagem , Adulto , Estudos de Casos e Controles , Diástole/fisiologia , Ecocardiografia Doppler de Pulso/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/diagnóstico por imagem , Valva Mitral/fisiopatologia , Linhagem , Fenótipo , Estudos Prospectivos , Valores de Referência , Medição de Risco , Sístole/fisiologia , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/genéticaRESUMO
This study investigated the effects of alcohol septal ablation (ASA) on microcirculatory function and myocardial energetics in patients with hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract (LVOT) obstruction. In 15 HCM patients who underwent ASA, echocardiography was performed before and 6 mo after the procedure to assess the LVOT gradient (LVOTG). Additionally, [(15)O]water PET was performed to obtain resting myocardial blood flow (MBF) and coronary vasodilator reserve (CVR). Changes in LV mass (LVM) and volumes were assessed by cardiovascular magnetic resonance imaging. Myocardial oxygen consumption (MVo(2)) was evaluated by [(11)C]acetate PET in a subset of seven patients to calculate myocardial external efficiency (MEE). After ASA, peak LVOTG decreased from 41 ± 32 to 23 ± 19 mmHg (P = 0.04), as well as LVM (215 ± 74 to 169 ± 63 g; P < 0.001). MBF remained unchanged (0.94 ± 0.23 to 0.98 ± 0.15 ml·min(-1)·g(-1); P = 0.45), whereas CVR increased (2.55 ± 1.23 to 3.05 ± 1.24; P = 0.05). Preoperatively, the endo-to-epicardial MBF ratio was lower during hyperemia compared with rest (0.80 ± 0.18 vs. 1.18 ± 0.15; P < 0.001). After ASA, the endo-to-epicardial hyperemic (h)MBF ratio increased to 1.03 ± 0.26 (P = 0.02). ΔCVR was correlated to ΔLVOTG (r = -0.82; P < 0.001) and ΔLVM (r = -0.54; P = 0.04). MEE increased from 15 ± 6 to 20 ± 9% (P = 0.04). Coronary microvascular dysfunction in obstructive HCM is at least in part reversible by relief of LVOT obstruction. After ASA, hMBF and CVR increased predominantly in the subendocardium. The improvement in CVR was closely correlated to the absolute reduction in peak LVOTG, suggesting a pronounced effect of LV loading conditions on microvascular function of the subendocardium. Furthermore, ASA has favorable effects on myocardial energetics.
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Técnicas de Ablação , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/cirurgia , Metabolismo Energético/fisiologia , Etanol , Septos Cardíacos/cirurgia , Microcirculação/fisiologia , Miocárdio/metabolismo , Algoritmos , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Circulação Coronária , Ecocardiografia , Endocárdio/fisiologia , Feminino , Hemodinâmica , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Consumo de Oxigênio , Pericárdio/fisiologia , Tomografia por Emissão de Pósitrons , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/cirurgia , Função Ventricular EsquerdaRESUMO
BACKGROUND: Diastolic dysfunction in hypertrophic cardiomyopathy (HCM) is accompanied by augmented left ventricular (LV) end-diastolic pressure, above all in the presence of LV outflow tract (LVOT) obstruction. Increased back-pressure may augment right ventricular (RV) afterload and induce an oxidative metabolic imbalance between the 2 ventricles. The aim was to study right-to-left ventricular oxidative metabolism in HCM and the effects of alcohol septal ablation (ASA). METHODS AND RESULTS: Twenty-one HCM patients were enrolled. Eleven healthy subjects served as a control group. Subjects underwent 2-dimensional echocardiography to assess LVOT gradient, left atrial size, and diastolic function. [(11)C]Acetate positron-emission tomography (PET) was performed to determine RVk(2) and LVk(2), as a noninvasive index of oxidative metabolism. Seven HCM patients with LVOT obstruction, scheduled to undergo ASA, were also studied 6 months after the procedure. RVk(2) was higher in HCM patients than i control subjects (0.081 ± 0.021 min(-1) vs. 0.061 ± 0.017 min(-1); P = .05), whereas LVk(2) was similar between groups. Consequently, RVk(2)/LVk(2) was increased in the patients (0.85 ± 0.19 vs 0.59 ± 0.13; P = .004). In patients with obstructive HCM, ASA reduced RVk(2) (0.085 ± 0.021 min(-1) to 0.072 ± 0.022 min(-1); P = .001). Inasmuch as LVk(2) remained unaffected by the procedure, RVk(2)/LVk(2) was decreased after ASA (0.66 ± 0.18; P = .03). The absolute change in LVOT gradient was related to the absolute change in RVk(2) (r = 0.77; P = .044). CONCLUSIONS: In HCM patients, RV oxygen consumption is increased in relation to the LV. ASA reduces RV oxygen consumption in HCM patients with LVOT obstruction, suggesting that increased LV loading conditions and diastolic dysfunction play a predominant role in augmenting RV workload in these patients.
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Técnicas de Ablação , Cardiomiopatia Hipertrófica/fisiopatologia , Etanol , Septos Cardíacos/cirurgia , Disfunção Ventricular Direita/fisiopatologia , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Estudos de Casos e Controles , Diástole , Ecocardiografia , Feminino , Hemodinâmica , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Disfunção Ventricular Direita/diagnóstico por imagemRESUMO
BACKGROUND: The wall motion score index (WMSI) is a surrogate for left ventricular ejection fraction (LV-EF), which becomes unreliable in poor echo windows. The value of contrast LV opacification (LVO) for WMSI assessment is not well known. OBJECTIVES: We sought to compare interobserver agreement for WMSI and the correlation between the LVO-WMSI and LV-EF using two-dimensional second harmonic (SH) and LVO echocardiography. METHODS: The study comprised 100 consecutive patients (57 ± 13 years, 85% males). Two independent physicians assessed LV segmental quality and wall motion for both the SH and LVO studies according to a 17-segment model. Systolic wall motion was defined as: normokinesia, hypokinesia (systolic inward endocardial motion <7 mm), akinesia, and dyskinesia. LV-EF was assessed from the LVO images according to the biplane modified Simpson's method. RESULTS: Of the 1,700 analyzed segments, 453 (26.6%) were poorly visualized with SH imaging, and 173 (10.2%) with LVO (P < 0.0001). The two observers agreed on segmental wall motion score in 1,299 segments (agreement 76%, Kappa 0.60) with SH imaging and in 1,491 segments (agreement 88%, Kappa 0.78) with LVO. Interobserver correlation (r(2) ) was 0.86 for the SH-WMSI and 0.93 for the LVO-WMSI. The limits-of-agreement for interobserver LVO-WMSI (mean difference -1.0%± 6.8%, agreement -14.6%, 12.6%) was lower than that for SH-WMSI (mean difference -2.3%± 10.1%, agreement -22.5, 17.9). The LVO-WMSI correlated well with LV-EF (r(2) = 0.71). LV-EF could be estimated according to the formula 1.01 - 0.32 × WMSI. CONCLUSION: Echo-contrast improves interobserver agreement for wall motion scoring and the WMSI. The LVO-imaged WMSI correlates well with LV-EF.
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Algoritmos , Ecocardiografia/métodos , Aumento da Imagem/métodos , Fosfolipídeos , Volume Sistólico , Hexafluoreto de Enxofre , Disfunção Ventricular Esquerda/diagnóstico por imagem , Meios de Contraste , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Mutations in the MYBPC3 gene, encoding cardiac myosin-binding protein C (cMyBP-C), are a frequent cause of familial hypertrophic cardiomyopathy. In the present study, we investigated whether protein composition and function of the sarcomere are altered in a homogeneous familial hypertrophic cardiomyopathy patient group with frameshift mutations in MYBPC3 (MYBPC3(mut)). METHODS AND RESULTS: Comparisons were made between cardiac samples from MYBPC3 mutant carriers (c.2373dupG, n=7; c.2864_2865delCT, n=4) and nonfailing donors (n=13). Western blots with the use of antibodies directed against cMyBP-C did not reveal truncated cMyBP-C in MYBPC3(mut). Protein expression of cMyBP-C was significantly reduced in MYBPC3(mut) by 33+/-5%. Cardiac MyBP-C phosphorylation in MYBPC3(mut) samples was similar to the values in donor samples, whereas the phosphorylation status of cardiac troponin I was reduced by 84+/-5%, indicating divergent phosphorylation of the 2 main contractile target proteins of the beta-adrenergic pathway. Force measurements in mechanically isolated Triton-permeabilized cardiomyocytes demonstrated a decrease in maximal force per cross-sectional area of the myocytes in MYBPC3(mut) (20.2+/-2.7 kN/m(2)) compared with donor (34.5+/-1.1 kN/m(2)). Moreover, Ca(2+) sensitivity was higher in MYBPC3(mut) (pCa(50)=5.62+/-0.04) than in donor (pCa(50)=5.54+/-0.02), consistent with reduced cardiac troponin I phosphorylation. Treatment with exogenous protein kinase A, to mimic beta-adrenergic stimulation, did not correct reduced maximal force but abolished the initial difference in Ca(2+) sensitivity between MYBPC3(mut) (pCa(50)=5.46+/-0.03) and donor (pCa(50)=5.48+/-0.02). CONCLUSIONS: Frameshift MYBPC3 mutations cause haploinsufficiency, deranged phosphorylation of contractile proteins, and reduced maximal force-generating capacity of cardiomyocytes. The enhanced Ca(2+) sensitivity in MYBPC3(mut) is due to hypophosphorylation of troponin I secondary to mutation-induced dysfunction.
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Cardiomiopatia Hipertrófica Familiar/genética , Cardiomiopatia Hipertrófica Familiar/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Adulto , Idoso , Biópsia , Cálcio/metabolismo , Feminino , Mutação da Fase de Leitura , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação/fisiologia , RNA Mensageiro/metabolismo , Sarcômeros/metabolismoRESUMO
PURPOSE: Next to hypertrophy, hypertrophic cardiomyopathy (HCM) is characterized by alterations in myocardial energetics. A small number of studies have shown that myocardial external efficiency (MEE), defined by external work (EW) in relation to myocardial oxidative metabolism (MVO(2)), is reduced. The present study was conducted to identify determinants of MEE in patients with HCM by use of dynamic positron emission tomography (PET) and cardiovascular magnetic resonance imaging (CMR). METHODS: Twenty patients with HCM (12 men, mean age: 55.2 + or - 13.9 years) and 11 healthy controls (7 men, mean age: 48.1 + or - 10 years) were studied with [(11)C]acetate PET to assess MVO(2). CMR was performed to determine left ventricular (LV) volumes and mass (LVM). Univariate and multivariate analyses were employed to determine independent predictors of myocardial efficiency. RESULTS: Between study groups, MVO(2) (controls: 0.12 + or - 0.04 ml x min(-1) x g(-1), HCM: 0.13 + or - 0.05 ml x min(-1) x g(-1), p = 0.64) and EW (controls: 9,139 + or - 2,484 mmHg x ml, HCM: 9,368 + or - 2,907 mmHg x ml, p = 0.83) were comparable, whereas LVM was significantly higher (controls: 99 + or - 21 g, HCM: 200 + or - 76 g, p < 0.001) and MEE was decreased in HCM patients (controls: 35 + or - 8%, HCM: 21 + or - 10%, p < 0.001). MEE was related to stroke volume (SV), LV outflow tract gradient, NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP) and serum free fatty acid levels (all p < 0.05). Multivariate analysis revealed that SV (ss = 0.74, p < 0.001) and LVM (ss = -0.43, p = 0.013) were independently related to MEE. CONCLUSION: HCM is characterized by unaltered MVO(2), impaired EW generation per gram of myocardial tissue and subsequent deteriorated myocardial efficiency. Mechanical external efficiency could independently be predicted by SV and LVM.
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Cardiomiopatia Hipertrófica/metabolismo , Coração/diagnóstico por imagem , Imageamento por Ressonância Magnética , Miocárdio/metabolismo , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/patologia , Ecocardiografia Doppler de Pulso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/fisiopatologia , Contração Miocárdica , Miocárdio/patologia , Consumo de Oxigênio , Obstrução do Fluxo Ventricular Externo/fisiopatologiaRESUMO
Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed.
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Inflamação/diagnóstico , Imagem Molecular/métodos , Placa Aterosclerótica/diagnóstico , Vasa Vasorum/patologia , Animais , Sistemas de Liberação de Medicamentos , Humanos , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Imageamento por Ressonância Magnética , Microbolhas , Neovascularização Fisiológica , Tomografia por Emissão de Pósitrons , Selectinas/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Vasa Vasorum/fisiologiaRESUMO
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.
Assuntos
Arteriosclerose/diagnóstico por imagem , Meios de Contraste , Hiperlipoproteinemia Tipo II/diagnóstico por imagem , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Vasa Vasorum/diagnóstico por imagem , Animais , Arteriosclerose/patologia , Modelos Animais de Doenças , Progressão da Doença , Hiperlipoproteinemia Tipo II/patologia , Cintilografia , Suínos , Fatores de Tempo , Túnica Íntima/patologia , Túnica Média/patologia , Ultrassonografia , Vasa Vasorum/patologiaRESUMO
BACKGROUND: Conceptually, an ideal therapeutic agent should target the underlying mechanisms that cause left ventricular (LV) diastolic dysfunction. The objective of our study was to gain further insight into the mechanics of diastology by comparison of LV untwisting measured by speckle tracking echocardiography (STE) in young healthy adults with normal and "pseudorestrictive" LV filling, and dilated cardiomyopathy (DCM) patients with "true restrictive" LV filling. METHODS: The study comprised 20 healthy volunteers with a Doppler LV-inflow pattern compatible with restrictive LV filling but a diastolic early phase filling velocity/early diastolic velocity of the mitral annulus (E/Em) ratio <8 ("pseudorestrictive"), 20 for age and gender-matched healthy volunteers with normal LV filling and an E/Em ratio <8, and 10 DCM patients with "true restrictive" LV filling and an E/Em ratio >15. LV untwisting parameters were determined by STE. RESULTS: Compared to healthy subjects, DCM patients had decreased peak diastolic untwisting velocity (-62 +/- 33 degrees/s vs -113 +/- 25 degrees/s, P < 0.01) and untwisting rate (-15 +/- 9 degrees/s vs -51 +/- 24 degrees/s, P < 0.01). Compared to healthy subjects with normal LV filling, healthy subjects with "pseudorestrictive" LV filling had increased peak diastolic untwisting velocity (-123 +/- 25 degrees/s vs -104 +/- 30 degrees/s, P < 0.05) and untwisting rate (-59 +/- 23 degrees/s vs -44 +/- 22 degrees/s, P < 0.05). CONCLUSION: Faster LV untwisting plays a pivotal role in the rapid early diastolic filling occasionally seen in young healthy individuals. In contrast, in DCM patients untwisting is severely delayed and this impairment to utilize suction may reduce LV filling.
Assuntos
Cardiomiopatia Dilatada/diagnóstico por imagem , Diástole , Ventrículos do Coração/diagnóstico por imagem , Valva Mitral/diagnóstico por imagem , Função Ventricular Esquerda , Adulto , Velocidade do Fluxo Sanguíneo , Cardiomiopatia Dilatada/fisiopatologia , Ecocardiografia , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Valva Mitral/fisiopatologia , Padrões de ReferênciaRESUMO
In this case report, a patient with a thrombus in a normal-sized and functional left ventricular is described. The thrombus was most likely formed during pheochromocytoma crisis with severe transient wall motion abnormalities.
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Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Feocromocitoma/complicações , Feocromocitoma/diagnóstico por imagem , Trombose/diagnóstico por imagem , Trombose/etiologia , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Adulto , Humanos , Masculino , UltrassonografiaRESUMO
AIMS: To investigate the outcome of cardiac evaluation and the risk stratification for sudden cardiac death (SCD) in asymptomatic hypertrophic cardiomyopathy (HCM) mutation carriers. METHODS AND RESULTS: Seventy-six HCM mutation carriers from 32 families identified by predictive DNA testing underwent cardiac evaluation including history, examination, electrocardiography, Doppler echocardiography, exercise testing, and 24 h Holter monitoring. The published diagnostic criteria for HCM in adult members of affected families were used to diagnose HCM. Thirty-three (43%) men and 43 (57%) women with a mean age of 42 years (range 16-79) were examined; in 31 (41%) HCM was diagnosed. Disease penetrance was age related and men were more often affected than women (P = 0.04). Myosin Binding Protein C (MYBPC3) mutation carriers were affected at higher age than Myosin Heavy Chain (MYH7) mutation carriers (P = 0.01). Risk factors for SCD were present in affected and unaffected carriers. CONCLUSION: Hypertrophic cardiomyopathy was diagnosed in 41% of carriers. Disease penetrance was age dependent, warranting repeated cardiologic evaluation. The MYBPC3 mutation carriers were affected at higher age than MYH7 mutation carriers. Risk factors for SCD were present in carriers with and without HCM. Follow-up studies are necessary to evaluate the effectiveness of risk stratification for SCD in this population.
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Cardiomiopatia Hipertrófica/genética , Morte Súbita Cardíaca/etiologia , Heterozigoto , Mutação/genética , Penetrância , Adolescente , Adulto , Idoso , Miosinas Cardíacas/genética , Proteínas de Transporte/genética , Feminino , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/genética , Linhagem , Medição de Risco , Adulto JovemRESUMO
Recently, echocardiography is the most widely used routine non-invasive diagnostic method, with which morphology and function of the mitral valve can be characterized. The aim of this review is to demonstrate the role of one of the newest echocardiographic developments, the transthoracic real-time three-dimensional echocardiography in the evaluation of mitral valve.
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Ecocardiografia Tridimensional , Valva Mitral/diagnóstico por imagem , Ecocardiografia Tridimensional/métodos , Humanos , Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/diagnóstico por imagem , Estenose da Valva Mitral/diagnóstico por imagemRESUMO
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.