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BACKGROUND: Hypertension (HTN) is common in patients with hypertrophic cardiomyopathy (HCM), but its effect on the treatment of left ventricular outflow tract (LVOT) obstruction is undefined. Although elevated systolic blood pressure (SBP) may impact dynamic LVOT gradients, its response to cardiac myosin inhibition is unknown. OBJECTIVES: In a post hoc exploratory analysis of the EXPLORER-HCM trial (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy), the authors examined the characteristics of patients with obstructive HCM and HTN and the associations between HTN, SBP, and the response to mavacamten treatment of LVOT obstruction. METHODS: Patients were stratified by baseline history of HTN and mean SBP during 30-week treatment with mavacamten or placebo. The study estimated treatment differences and evaluated HTN and SBP groups by treatment interaction. Analysis of covariance was used to model changes in continuous endpoints, and a generalized linear model was used for binary endpoints. RESULTS: HTN was present in 119 of 251 patients (47.4%), including 60 receiving mavacamten and 59 receiving placebo. Patients with HTN vs no HTN were older (63.4 vs 54.0 years; P < 0.001), had higher SBP (134 ± 15.1 mm Hg vs 123 ± 13.8 mm Hg; P < 0.001), more comorbidities, and lower peak oxygen consumption (19 ± 3 vs 20 ± 4 mL/kg/min; P = 0.021). Patients with HTN had similar NYHA functional class (NYHA functional class II, 72% vs 73%), Valsalva LVOT gradients (72 ± 34 mm Hg vs 74 ± 30 mm Hg), Kansas City Cardiomyopathy Questionnaire-Clinical Summary Scores (70.6 ± 18.8 vs 68.9 ± 23.1), and NT pro-B-type natriuretic peptide levels (geometric mean 632 ± 129 pg/mL vs 745 ± 130 pg/mL). Mavacamten-treated patients had improvement in all primary, secondary, and exploratory endpoints regardless of HTN status or mean SBP. CONCLUSIONS: The clinical benefits of mavacamten in symptomatic, obstructive HCM were similar in patients with and without HTN, despite differences in baseline characteristics. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy [EXPLORER-HCM]; NCT03470545).
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Cardiomiopatia Hipertrófica , Insuficiência Cardíaca , Hipertensão , Uracila , Adulto , Humanos , Benzilaminas/efeitos adversos , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Uracila/análogos & derivadosRESUMO
Aortic stenosis (AS) is the most common age-related valvular condition with a prevalence of 13.1% in patients older than 75 years of age. Based on the severity of AS and symptoms, current guidelines recommend interval monitoring with transthoracic echocardiogram (TTE). However, no guidelines exist regarding screening asymptomatic persons for AS. Prevalence of AS is comparable to conditions such as colorectal cancer, lung cancer, breast cancer, and abdominal aortic aneurysm where dedicated screening programs are offered resulting in reduction of overall morbidity and mortality. We review recent advancements in treatment options, and we propose an AS screening program for high-risk individuals without known history of AS including all persons over age 75 and persons aged 70 years and older with dialysis dependent end-stage renal disease (ESRD).
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BACKGROUND: EXPLORER-HCM (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac myosin inhibitor, improves symptoms, exercise capacity, and left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM). OBJECTIVES: The purpose of this study was to evaluate mavacamten's effect on measures of cardiac structure and function and its association with changes in other clinical measures. METHODS: Key echocardiographic parameters from serial echocardiograms over 30 weeks from 251 symptomatic oHCM patients (mavacamten [n = 123], placebo [n = 128]) were assessed in a core laboratory. RESULTS: More patients on mavacamten (80.9%; n = 76 of 94) vs placebo (34.0%; n = 33 of 97) showed complete resolution of mitral valve systolic anterior motion after 30 weeks (difference, 46.8%; P < 0.0001). Mavacamten also improved measures of diastolic function vs placebo, including left atrial volume index (LAVI) (mean ± SD baseline: 40 ± 12 mL/m2 vs 41 ± 14 mL/m2; mean change from baseline of -7.5 mL/m2 [95% CI: -9.0 to -6.1 mL/m2] vs -0.09 mL/m2 [95% CI: -1.6 to 1.5 mL/m2]; P < 0.0001) and lateral E/e' (baseline, 15 ± 6 vs 15 ± 8; change of -3.8 [95% CI: -4.7 to -2.8] vs 0.04 [95% CI: -0.9 to 1.0]; P < 0.0001). Among mavacamten-treated patients, improvement in resting, Valsalva, and post-exercise LVOT gradients, LAVI, and lateral E/e' was associated with reduction in N-terminal pro-B-type natriuretic peptide (P ≤ 0.03 for all). Reduction in LAVI was associated with improved peak exercise oxygen consumption (P = 0.04). CONCLUSIONS: Mavacamten significantly improved measures of left ventricular diastolic function and systolic anterior motion. Improvement in LVOT obstruction, LAVI, and E/e' was associated with reduction in a biomarker of myocardial wall stress (N-terminal pro-B-type natriuretic peptide). These findings demonstrate improvement in important markers of the pathophysiology of oHCM with mavacamten. (Clinical Study to Evaluate Mavacamten [MYK-461] in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545).
Assuntos
Benzilaminas/uso terapêutico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Coração/efeitos dos fármacos , Uracila/análogos & derivados , Idoso , Benzilaminas/farmacologia , Biomarcadores/sangue , Miosinas Cardíacas/antagonistas & inibidores , Cardiomiopatia Hipertrófica/sangue , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Método Duplo-Cego , Ecocardiografia , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Uracila/farmacologia , Uracila/uso terapêuticoRESUMO
BACKGROUND: Septic cardiomyopathy (SCM) is common in sepsis and associated with increased morbidity and mortality. Left ventricular global longitudinal strain (LV GLS), measured by speckle tracking echocardiography, allows improved identification of impaired cardiac contractility. The peripheral blood transcriptome may be an important window into SCM pathophysiology. We therefore studied the peripheral blood transcriptome and LV GLS in a prospective cohort of patients with sepsis. RESULTS: In this single-center observational pilot study, we enrolled adult patients (age > 18) with sepsis within 48 h of admission to the ICU. SCM was defined as LV GLS > - 17% based on echocardiograms performed within 72 h of admission. We enrolled 27 patients, 24 of whom had high-quality RNA results; 18 (75%) of 24 had SCM. The group was 50% female and had a median (IQR) age of 59.5 (48.5-67.0) years and admission APACHE II score of 21.0 (16.0-32.3). Forty-six percent had septic shock. After filtering for low-expression and non-coding genes, 15,418 protein coding genes were expressed and 73 had significantly different expression between patients with vs. without SCM. In patients with SCM, 43 genes were upregulated and 30 were downregulated. Pathway analysis identified enrichment in type 1 interferon signaling (adjusted p < 10-5). CONCLUSIONS: In this hypothesis-generating study, SCM was associated with upregulation of genes in the type 1 interferon signaling pathway. Interferons are cytokines that stimulate the innate and adaptive immune response and are implicated in the early proinflammatory and delayed immunosuppression phases of sepsis. While type 1 interferons have not been implicated previously in SCM, interferon therapy (for viral hepatitis and Kaposi sarcoma) has been associated with reversible cardiomyopathy, perhaps suggesting a role for interferon signaling in SCM.
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BACKGROUND: Diastolic dysfunction (DD) identified on echocardiography predicts mortality after cardiac surgery, however the most useful diastolic parameters for assessment and the association of DD with prolonged mechanical ventilation, ICU re-admission, and hospital length of stay are not established. METHODS: We included patients that underwent coronary artery bypass grafting (CABG), aortic valve replacement (AVR) or a combined procedure (CAB-AVR) from 2010 to 2016, and who had preoperative transthoracic echocardiography (TTE) at our institution within 6 months of the operation. Diastolic function was graded using the transmitral E and A waves and the septal tissue Doppler velocity. We performed logistic regression to assess the association of grade of DD with a composite endpoint of death, prolonged mechanical ventilation, ICU readmission during hospitalization, and hospital length of stay longer than 14 days. RESULTS: Between 2010 and 2016, 577 patients were eligible for inclusion. DD was common, with 42% of the cohort manifesting grade II or grade III DD. Rates of death and prolonged ventilation increased across grades of DD and across quartiles of increasing LV filling pressure, assessed by the E/e' ratio. Adjusting for age, sex, procedure, systolic and diastolic function, both systolic (odds ratio 0.68 95% CI 0.55-0.85 per inter-quartile increase in LVEF) and diastolic function (odds ratio 1.31 95% CI 1.04-1.66 per increasing DD grade) both independently predicted outcome. CONCLUSION: Diastolic dysfunction is common among patients undergoing cardiac surgery and is associated with death, prolonged mechanical ventilation, and prolonged hospital and ICU length of stay independent of systolic dysfunction.
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Ponte de Artéria Coronária , Implante de Prótese de Valva Cardíaca , Disfunção Ventricular Esquerda/diagnóstico , Idoso , Valva Aórtica/cirurgia , Ponte de Artéria Coronária/mortalidade , Ecocardiografia Doppler , Feminino , Implante de Prótese de Valva Cardíaca/mortalidade , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Disfunção Ventricular Esquerda/complicações , Disfunção Ventricular Esquerda/epidemiologiaRESUMO
Importance: Considerable research has described the arrhythmic course of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, objective data characterizing structural progression, such as ventricular enlargement and cardiac dysfunction, in ARVD/C are relatively scarce. Objectives: To define the extent of structural progression, identify determinants of structural progression, and determine the association between structural progression and electrocardiographic (ECG) changes in patients with ARVD/C. Design, Setting, and Participants: In this cohort study, first- and last-available echocardiograms of 85 patients with ARVD/C fulfilling 2010 Task Force diagnostic criteria (TFC) from a transatlantic ARVD/C registry were retrospectively compared to assess structural disease progression. Right ventricular (RV) size and systolic function between baseline and last follow-up were compared. The RV size was determined by RV outflow tract dimension, and RV and left ventricular (LV) systolic function were determined by RV fractional area change (RV-FAC) and LV ejection fraction (LVEF), respectively. Multivariable logistic regression was used to study associations between baseline characteristics and the occurrence of structural progression. Main Outcomes and Measures: The main outcome was the change in variables indicating structural progression. Secondary outcomes were the correlation with electrical progression and identification of the association between baseline characteristics and occurence structural progression. Results: Among the 85 patients with ARVD/C, mean (SD) age at baseline was 42.8 (14.4) years and 47 (55%) were men. After a mean (SD) follow-up of 6.4 (2.5) years, RV outflow tract dimension increased from 35 mm (interquartile range [IQR], 31 to 39) to 37 mm (IQR, 33 to 41) (P < .001), RV-FAC decreased from 39% (IQR, 33% to 44%) to 34% (IQR, 24% to 42%) (P < .001) (rate -3.3% per 5 years; IQR, -8.9% to 1.2%), indicating large interpatient variability. The LVEF decreased from 55% (IQR, 52% to 60%) to 54% (IQR, 49% to 57%) (P = .001) (rate, -0.2% per 5 years; IQR, -6.5% to 1.7%). Forty examinations were reanalyzed to establish the measurement error. Patients exceeding the measurement error by ±2 SDs were identified with significant progressive disease for RV, with a decrease in RV-FAC greater than 10% (n = 21) and, for LV, a decrease in LVEF greater than 7% (n = 23). Progression of RV disease was associated with depolarization criteria at baseline (odds ratio [OR], 9.0; 95% CI, 1.1-74.2; P = .04), whereas progression of LV disease was associated with phospholamban (PLN) mutation (OR, 8.8; 95% CI, 2.1-37.2; P = .003). There was no association between progressive RV/LV structural disease and newly developed ECG TFC. Conclusions and Relevance: Structural dysfunction in ARVD/C is progressive with substantial interpatient variability. Significant structural RV progression was associated with prior depolarization abnormalities, whereas LV progression is modified by genetic background. Structural progression was not associated with development of new ECG TFC. The results of this study pave the way for designing and launching trials aimed at reducing structural progression in patients with ARVD/C.
Assuntos
Displasia Arritmogênica Ventricular Direita/diagnóstico , Eletrocardiografia , Sistema de Condução Cardíaco/fisiopatologia , Função Ventricular Direita/fisiologia , Adulto , Displasia Arritmogênica Ventricular Direita/fisiopatologia , Progressão da Doença , Ecocardiografia , Feminino , Seguimentos , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de TempoRESUMO
Vasodilator-induced transient left ventricular (LV) cavity dilation by positron emission tomography (PET) is common in patients with hypertrophic cardiomyopathy (HC). Because most patients with PET-LV cavity dilation lack obstructive epicardial coronary artery disease, we hypothesized that vasodilator-induced subendocardial hypoperfusion resulting from microvascular dysfunction underlies this result. To test this hypothesis, we quantified myocardial blood flow (MBF) (subepicardial, subendocardial, and global MBF) and left ventricular ejection fraction (LVEF) in 104 patients with HC without significant coronary artery disease, using 13NH3-PET. Patients with HC were divided into 2 groups, based on the presence/absence of LV cavity dilation (LVvolumestress/LVvolumerest >1.13). Transient PET-LV cavity dilation was evident in 52% of patients with HC. LV mass, stress left ventricular outflow tract gradient, mitral E/E', late gadolinium enhancement, and prevalence of ischemic ST-T changes after vasodilator were significantly higher in patients with HC with LV cavity dilation. Baseline LVEF was similar in the 2 groups, but LV cavity dilation+ patients had lower stress-LVEF (43 ± 11 vs 53 ± 10; p <0.001), lower stress-MBF in the subendocardial region (1.6 ± 0.7 vs 2.3 ± 1.0 ml/min/g; p <0.001), and greater regional perfusion abnormalities (summed difference score: 7.0 ± 6.1 vs 3.9 ± 4.3; p = 0.004). The transmural perfusion gradient, an indicator of subendocardial perfusion, was similar at rest in the 2 groups. Notably, LV cavity dilation+ patients had lower stress-transmural perfusion gradients (0.85 ± 0.22, LV cavity dilation+ vs 1.09 ± 0.39, LV cavity dilation-; p <0.001), indicating vasodilator-induced subendocardial hypoperfusion. The stress-transmural perfusion gradient, global myocardial flow reserve, and stress-LVEF were associated with LV cavity dilation. In conclusion, diffuse subendocardial hypoperfusion and myocardial ischemia resulting from microvascular dysfunction contribute to development of transient LV cavity dilation in HC.
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Cardiomiopatia Hipertrófica/diagnóstico por imagem , Circulação Coronária , Ventrículos do Coração/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico por imagem , Volume Sistólico , Adulto , Idoso , Amônia , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/fisiopatologia , Imagem de Perfusão do Miocárdio , Radioisótopos de Nitrogênio , Tomografia por Emissão de Pósitrons , Compostos RadiofarmacêuticosRESUMO
Although rare, hypertrophic cardiomyopathy (HCM) with midventricular obstruction is often associated with severe symptoms and complications. None of the existing HCM animal models display this particular phenotype. Our group developed a mouse line that overexpresses the ErbB2 receptor (ErbB2(tg)) in cardiomyocytes; we previously showed that the ErbB2 receptor induces cardiomyocyte hypertrophy, myocyte disarray, and fibrosis compatible with HCM. In the current study, we sought to further echocardiographically characterize the ErbB2(tg) mouse line as a model of HCM. Compared with their wild-type littermates, ErbB2(tg) mice show increased left ventricular (LV) mass, concentric LV hypertrophy, and papillary muscle hypertrophy. This hypertrophy was accompanied by diastolic dysfunction, expressed as reduced E:A ratio, prolonged deceleration time, and elevated E:e' ratio. In addition, ErbB2(tg) mice consistently showed midcavity obstruction with elevated LV gradients, and the flow profile revealed a prolonged pressure increase and a delayed peak, indicating dynamic obstruction. The ejection fraction was increased in ErbB2(tg) mice, due to reduced end-diastolic and end-systolic LV volumes. Furthermore, systolic radial strain and systolic radial strain rate but not systolic circumferential strain and longitudinal strain were decreased in ErbB2(tg) compared with wild-type mice. In conclusion, the phenotype of the ErbB2(tg) mouse model is consistent with midventricular HCM in many important aspects, including massive LV hypertrophy, diastolic dysfunction, and midcavity obstruction. This pattern is unique for a small animal model, suggesting that ErbB2(tg) mice may be well suited for research into the hemodynamics and treatment of this rare form of HCM.
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Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/etiologia , Receptor ErbB-2/genética , Animais , Cardiomiopatia Hipertrófica/fisiopatologia , Diástole , Modelos Animais de Doenças , Ecocardiografia Doppler em Cores , Ecocardiografia Doppler de Pulso , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Músculos Papilares/diagnóstico por imagem , Músculos Papilares/patologia , Receptor ErbB-2/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , SístoleRESUMO
BACKGROUND: Apparent left ventricular cavity dilatation (LVCD) in patients with hypertrophic cardiomyopathy (HCM) is an incompletely understood phenomenon. We aimed at investigating its clinical predictors and potential mechanisms. METHODS: Sixty one HCM patients underwent N-13-ammonia PET for visual evaluation of LVCD, transient ischemic dilatation (TID) index, myocardial blood flow (MBF), coronary flow reserve (CFR), and regional myocardial perfusion (rMP). TID index was also derived at 2-4 and 15-20 minutes. RESULTS: Visual LVCD and quantitative TID (>1.13 abnormal) agreement were excellent (k 0.91; P < .0001). LVCD-positive (n = 32) patients had greater LV thickness (2.26 ± 0.59 vs 1.92 ± 0.41 cm; P = .005), but lower stress MBF (1.66 ± 0.42 vs 2.07 ± 0.46 mL/minute/g; P < .0001), and CFR (1.90 ± 0.46 vs 2.46 ± 0.69; P < .0001) than LVCD-negative (n = 29) patients. Abnormal rMP was present in 31/32 LVCD-positive but only 12/29 (P < .0001) LVCD-negative. TID index was higher at 2-4 (1.30 ± 0.13) than at 15-20 minutes (1.27 ± 0.12; P = .001) in LVCD-positive, whereas it was the same (1.04 ± 0.07 vs 1.04 ± 0.07; P = .9) in LVCD-negative. In multivariate analysis, global peak MBF, abnormal rMP, and LV thickness were the best predictors of LVCD. CONCLUSION: Apparent LVCD is a common finding in HCM, intimately related to abnormal myocardial perfusion, globally impaired vasodilator flow reserve, and degree of hypertrophy. In addition to regional and/or diffuse subendocardial ischemia, some degree of true LV chamber dilatation may also contribute to the occurrence of apparent LVCD in HCM.
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Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/epidemiologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/epidemiologia , Imagem de Perfusão do Miocárdio/estatística & dados numéricos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/estatística & dados numéricos , Baltimore/epidemiologia , Comorbidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e EspecificidadeRESUMO
Hydrogen sulfide (H2S) has emerged as an important gasotransmitter in the vasculature. In this study, we tested the hypothesis that H2S contributes to coronary vasoregulation and evaluated the physiological relevance of two sources of H2S, namely, cystathionine-γ-lyase (CSE) and 3-mercaptypyruvate sulfertransferase (MPST). MPST was detected in human coronary artery endothelial cells as well as rat and mouse coronary artery; CSE was not detected in the coronary vasculature. Rat coronary artery homogenates produced H2S through the MPST pathway but not the CSE pathway in vitro. In vivo coronary vasorelaxation response was similar in CSE knockout mice, wild-type mice (WT), and WT mice treated with the CSE inhibitor propargylglycine, suggesting that CSE-produced H2S does not have a significant role in coronary vasoregulation in vivo. Ex vivo, the MPST substrate 3-mercaptopyruvate (3-MP) and H2S donor sodium hydrosulfide (NaHS) elicited similar coronary vasoreactivity responses. Pyruvate did not have any effects on vasoreactivity. The vasoactive effect of H2S appeared to be nitric oxide (NO) dependent: H2S induced coronary vasoconstriction in the presence of NO and vasorelaxation in its absence. Maximal endothelial-dependent relaxation was intact after 3-MP and NaHS induced an increase in preconstriction tone, suggesting that endothelial NO synthase activity was not significantly inhibited. In vitro, H2S reacted with NO, which may, in part explain the vasoconstrictive effects of 3-MP and NaHS. Taken together, these data show that MPST rather than CSE generates H2S in coronary artery, mediating its effects through direct modulation of NO. This has important implications for H2S-based therapy in healthy and diseased coronary arteries.
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Vasos Coronários/enzimologia , Cistationina gama-Liase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Sulfurtransferases/metabolismo , Animais , Células Cultivadas , Vasos Coronários/efeitos dos fármacos , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/deficiência , Cistationina gama-Liase/genética , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Masculino , Camundongos Knockout , Óxido Nítrico/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologiaRESUMO
A localized hypertrophy of the subaortic segment of the ventricular septum-ventricular septal bulge (VSB)-has been frequently described in series of elderly population, but its prevalence with age, clinical correlates, and impact on cardiac function and exercise capacity remain uncertain. We explored these associations in a cross-sectional sample without known cardiac disease from the Baltimore Longitudinal Study of Aging. We randomly selected 700 participants (50% men, mean age 64 ± 15, range 26 to 95 years) and reviewed their echocardiograms. We identified 28 men and 21 women with VSB (7% overall prevalence). The prevalence of VSB significantly increased with age in both genders (p <0.0001). In multivariate logistic regression including hypertension and other cardiovascular risk factors, only age displayed a significant independent association with VSB (OR 1.06 per year, 95% confidence interval 1.03 to 1.10, p = 0.0001). After multiple adjustments, participants with VSB compared with those without had enhanced global left ventricular contractility (fractional shortening 41 ± 1.3 vs 38 ± 0.3%, p = 0.04; ejection fraction 71 ± 1.6 vs 67 ± 0.4%, p = 0.06; systolic velocity of the mitral annulus 8.4 ± 0.1 vs 8.9 ± 0.3, p = 0.06), and larger aortic root diameters (3.3 ± 0.06 vs 3.1 ± 0.02 cm, p = 0.02). In subgroup of participants who completed a maximal treadmill test (177 women and 196 men), those with VSB (19, 5.1%) had significantly lower peak oxygen consumption than their counterparts (19.6 ± 3.8 vs 22.9 ± 6.6 ml/kg/min, p = 0.03). However, this association was no longer significant after multiple adjustments. In conclusion, the presence of VSB is independently associated with older age and determines enhanced left ventricular contractility, without any evident impact on exercise capacity.
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Envelhecimento , Septos Cardíacos/fisiopatologia , Hipertrofia Ventricular Esquerda/epidemiologia , Função Ventricular Esquerda/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Baltimore/epidemiologia , Ecocardiografia , Tolerância ao Exercício , Feminino , Seguimentos , Septos Cardíacos/diagnóstico por imagem , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Fatores de TempoRESUMO
We have examined, for the first time, the effects of the familial hypertrophic cardiomyopathy (HCM)-associated Lys104Glu mutation in the myosin regulatory light chain (RLC). Transgenic mice expressing the Lys104Glu substitution (Tg-MUT) were generated and the results were compared to Tg-WT (wild-type human ventricular RLC) mice. Echocardiography with pulse wave Doppler in 6month-old Tg-MUT showed early signs of diastolic disturbance with significantly reduced E/A transmitral velocities ratio. Invasive hemodynamics in 6month-old Tg-MUT mice also demonstrated a borderline significant prolonged isovolumic relaxation time (Tau) and a tendency for slower rate of pressure decline, suggesting alterations in diastolic function in Tg-MUT. Six month-old mutant animals had no LV hypertrophy; however, at >13months they displayed significant hypertrophy and fibrosis. In skinned papillary muscles from 5 to 6month-old mice a mutation induced reduction in maximal tension and slower muscle relaxation rates were observed. Mutated cross-bridges showed increased rates of binding to the thin filaments and a faster rate of the power stroke. In addition, ~2-fold lower level of RLC phosphorylation was observed in the mutant compared to Tg-WT. In line with the higher mitochondrial content seen in Tg-MUT hearts, the MUT-myosin ATPase activity was significantly higher than WT-myosin, indicating increased energy consumption. In the in vitro motility assay, MUT-myosin produced higher actin sliding velocity under zero load, but the velocity drastically decreased with applied load in the MUT vs. WT myosin. Our results suggest that diastolic disturbance (impaired muscle relaxation, lower E/A) and inefficiency of energy use (reduced contractile force and faster ATP consumption) may underlie the Lys104Glu-mediated HCM phenotype.
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Cardiomiopatia Hipertrófica/genética , Mutação , Miócitos Cardíacos/metabolismo , Cadeias Leves de Miosina/genética , Músculos Papilares/metabolismo , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/metabolismo , Cardiomiopatia Hipertrófica/patologia , Diástole , Regulação da Expressão Gênica , Frequência Cardíaca , Masculino , Camundongos , Camundongos Transgênicos , Dados de Sequência Molecular , Relaxamento Muscular , Contração Miocárdica , Miócitos Cardíacos/patologia , Cadeias Leves de Miosina/metabolismo , Músculos Papilares/diagnóstico por imagem , Músculos Papilares/patologia , Cultura Primária de Células , Transdução de Sinais , Técnicas de Cultura de Tecidos , Ultrassonografia Doppler de PulsoRESUMO
The development of left ventricular hypertrophy and dysfunction in aortic regurgitation (AR) has only been sparsely studied experimentally. In a new model of chronic AR in rats, we examined activation of molecular pathways involved in myocardial hypertrophy. Chronic AR was produced by damaging one or two valve cusps, resulting in eccentric remodeling and left ventricular dysfunction, with no increase in overall fibrosis. Western blotting showed increased activation of Akt and p38 at 12 weeks and of c-Jun amino-terminal kinase at 2 weeks, decreased activation of extracellular regulated kinase 5 at both 2 and 12 weeks, while activation of calcium/calmodulin-dependent protein kinase II and extracellular regulated kinase 1/2 was unchanged. Expression of calcineurin and ANF was also unchanged. Eccentric hypertrophy and early cardiac dysfunction in experimental AR are associated with a pattern of activation of intracellular pathways different from that seen with pathological hypertrophy in pressure overload, and more similar to that associated with benign physiological hypertrophy.
Assuntos
Insuficiência da Valva Aórtica/complicações , Hipertrofia Ventricular Esquerda/etiologia , Miocárdio/metabolismo , Transdução de Sinais , Disfunção Ventricular Esquerda/etiologia , Animais , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/metabolismo , Insuficiência da Valva Aórtica/fisiopatologia , Fator Natriurético Atrial/metabolismo , Calcineurina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Doença Crônica , Modelos Animais de Doenças , Ecocardiografia Doppler em Cores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/fisiopatologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Miocárdio/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac ß-myosin heavy chain gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetics have not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate supplied by the creatine kinase (CK) reaction and phosphocreatine, the heart's primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by the Arg403GIn mutation and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 patients with HC. The patients with HC had impairment of diastolic function and mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial phosphocreatine was significantly decreased by 24% in patients (7.1 ± 2.3 µmol/g) compared with the controls (9.4 ± 1.2 µmol/g; p = 0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28 ± 0.15 vs 0.38 ± 0.07 s⻹, p = 0.035) and the forward CK flux was 44% lower (2.0 ± 1.4 vs 3.6 ± 0.9 µmol/g/s, p = 0.001) than in the controls. The contractile abnormalities did not correlate with the metabolic indexes. In conclusion, myocardial phosphocreatine and CK-ATP delivery are significantly reduced in patients with HC caused by the Arg403Gln mutation, akin to previous results from mice with the same mutation. A lack of a relation between energetic and contractile abnormalities suggests the former result from the sarcomeric mutation and not a late consequence of mechanical dysfunction.
Assuntos
Trifosfato de Adenosina/sangue , Cardiomiopatia Hipertrófica/sangue , Creatina Quinase/sangue , Metabolismo Energético , Fosfocreatina/sangue , Adulto , Cardiomiopatia Hipertrófica/genética , Cardiomiopatia Hipertrófica/fisiopatologia , DNA/genética , Análise Mutacional de DNA , Progressão da Doença , Ecocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Mutação , Cadeias Pesadas de Miosina/genética , PrognósticoRESUMO
Tissue engineering-based approaches have the potential to improve stem cell engraftment by increasing cell delivery to the myocardium. Our objective was to develop and characterize a naturally-derived, autologous, biodegradable hydrogel in order to improve acute stem cell retention in the myocardium. HA-blood hydrogels (HA-BL) were synthesized by mixing in a 1:1(v/v) ratio, lysed whole blood and hyaluronic acid (HA), whose carboxyl groups were functionalized with N-hydroxysuccinimide (NHS) to yield HA succinimidyl succinate (HA-NHS). We performed physical characterization and measured survival/proliferation of cardiosphere-derived cells (CDCs) encapsulated in the hydrogels. Hydrogels were injected intra-myocardially or applied epicardially in rats. NHS-activated carboxyl groups in HA react with primary amines present in blood and myocardium to form amide bonds, resulting in a 3D hydrogel bound to tissue. HA-blood hydrogels had a gelation time of 58±12 s, swelling ratio of 10±0.5, compressive and elastic modulus of 14±3 and 1.75±0.6 kPa respectively. These hydrogels were not degraded at 4 wks by hydrolysis alone. CDC encapsulation promoted their survival and proliferation. Intra-myocardial injection of CDCs encapsulated in these hydrogels greatly increased acute myocardial retention (p=0.001). Epicardial application of HA-blood hydrogels improved left ventricular ejection fraction following myocardial infarction (p=0.01). HA-blood hydrogels are highly adhesive, biodegradable, promote CDC survival and increase cardiac function following epicardial application after myocardial infarction.
Assuntos
Células Sanguíneas/química , Ácido Hialurônico/química , Hidrogéis/química , Miocárdio/citologia , Plasma/química , Transplante de Células-Tronco , Alicerces Teciduais/química , Animais , Células Sanguíneas/metabolismo , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Módulo de Elasticidade , Feminino , Humanos , Ácido Hialurônico/metabolismo , Hidrogéis/metabolismo , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/cirurgia , Miocárdio/patologia , Plasma/metabolismo , Ratos , Ratos Endogâmicos WKY , Ratos Nus , Succinimidas/químicaRESUMO
Dipyridamole is the most common vasodilator used with positron emission tomography for the evaluation of patients with hypertrophic cardiomyopathy (HC). The aim of this study was to evaluate whether positron emission tomographic quantification of regional myocardial perfusion (rMP), myocardial blood flow (MBF), and coronary flow reserve are comparable between dipyridamole and the newer vasodilator regadenoson in HC. An additional aim was to evaluate the association between vasodilator-induced ST-segment depression on electrocardiography and myocardial flow in HC. Nitrogen-13 ammonia positron emission tomography was performed in 57 patients with symptomatic HC at rest and during vasodilator stress (peak) with either dipyridamole (0.56 mg/kg during 4-minute infusion) or regadenoson (0.4 mg fixed bolus dose) for assessment of electrocardiographic findings, rMP (17-segment American Heart Association summed difference score), MBF, and coronary flow reserve. The dipyridamole and regadenoson groups consisted of 28 and 29 patients respectively. Baseline characteristics, including rest MBF (0.92 ± 0.22 vs 0.89 ± 0.23 ml/min/g, p = 0.60), were similar between the 2 groups. During stress, the presence and severity of abnormal rMP (summed difference score 5.5 ± 5.5 vs 5.8 ± 6.7, p = 0.80), peak MBF (1.81 ± 0.44 vs 1.82 ± 0.50 ml/min/g, p = 0.90), and coronary flow reserve (2.02 ± 0.53 vs 2.12 ± 0.12, p = 0.50) were comparable between the dipyridamole and regadenoson groups. Fewer patients exhibited side effects with regadenoson (2 vs 7, p = 0.06). Vasodilator-induced ST-segment depression showed high specificity (about 92%) but low sensitivity (about 34%) to predict abnormal rMP (summed difference score ≥2). In conclusion, measurement of rMP and quantitative flow with positron emission tomography is similar between regadenoson and dipyridamole in patients with symptomatic HC. Regadenoson is tolerated better than dipyridamole and is easier to administer. Vasodilator-induced ST-segment depression is a specific but nonsensitive marker for the prediction of abnormal rMP in patients with HC.
Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Circulação Coronária/efeitos dos fármacos , Dipiridamol , Eletrocardiografia/efeitos dos fármacos , Teste de Esforço/métodos , Tomografia por Emissão de Pósitrons/métodos , Purinas , Pirazóis , Antagonistas do Receptor A2 de Adenosina/administração & dosagem , Cardiomiopatia Hipertrófica/fisiopatologia , Dipiridamol/administração & dosagem , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Curva ROC , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Volume Sistólico/efeitos dos fármacos , Vasodilatadores/administração & dosagemRESUMO
Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving ß-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and ß-adrenergic receptor sarcomere and calcium responses, particularly the ß2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gαi signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling (RGS2, RGS3), yielding Gαs-biased ß2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum-localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased ß2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored ß-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.
Assuntos
Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/terapia , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/fisiologia , Animais , Terapia de Ressincronização Cardíaca , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Cães , Transferência Ressonante de Energia de Fluorescência , Proteínas de Ligação ao GTP/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Humanos , Técnicas In Vitro , Células Musculares/metabolismo , Miocárdio/metabolismo , Proteínas RGS/metabolismoRESUMO
Hypoxia-inducible factor-1alpha (HIF-1α) expression promotes angiogenesis and can influence stem cell engraftment. We investigated the effect of stable over-expression of constitutively active HIF-1α on cardiosphere-derived cell (CDC) engraftment and left ventricular function. CDCs were transduced with a lentivirus expressing a constitutively active mutant of human HIF-1α (LVHIF-1α). Two million male rat CDCs were injected into the infarct following ligation of the mid-LAD in female syngeneic rats. Left ventricular ejection fraction (EF) and circumferential strain were measured by echocardiography at 1 and 4 weeks post-MI in the following groups: PBS group (n = 7), CELL group (n = 7), and CELL-HIF group (n = 7). HIF-1α, VEGF, endothelin-1 expression, and CDC engraftment were measured by quantitative PCR. At 30 days, EF was unchanged in the CELL-HIF group (p = NS), increased in the CELL group (p = 0.025), and decreased in the PBS group (p = 0.021), but engraftment was similar (2.4% ± 3.3% vs 1.7% ± 0.8%, p = NS). Mean circumferential strain of the infarcted region was unchanged in the CELL-HIF group, but improved in the CELL group (p = 0.02). Endothelin-1 and VEGF expression were higher in HIF-CDCs exposed to hypoxia, compared with non-transduced CDCs. HIF-1α expression in CDCs blunted the beneficial functional effects of CDC transplantation, suggesting that paracrine factor balance may play an important role in cardiac regeneration.