RESUMO
BACKGROUND: Intraleaflet hematomas are associated with advanced stages of aortic valve calcification and suspected to be involved in disease progression. However, the mechanism by which the entry of blood cells into the valves affects the biology of aortic valvular interstitial cells (VICs) remains to be elucidated. OBJECTIVES: This study sought to evaluate the putative link between intraleaflet hematoma and aortic valve calcification and to assess its pathophysiological implications. METHODS: The spatial relationship between calcium deposits and intraleaflet hematomas was analyzed by whole-mount staining of calcified and noncalcified human aortic valves, obtained in the context of heart transplantation and from patients who underwent surgical valve replacement. Endothelial microfissuring was evaluated by en face immunofluorescence and scanning electron microscopic analyses of the fibrosa surface. Red blood cell (RBC) preparations were used in vitro to assess, by immunofluorescence microscopy and Alizarin red staining, the potential impact of intraleaflet hematomas on phenotypic changes in VICs. RESULTS: Intraleaflet hematomas, revealed by iron deposits and RBCs into the fibrosa, secondary to endothelial microfissuring, were consistently found in noncalcified valves. The contact of primary VICs derived from these valves with RBCs resulted in a global inflammatory and osteoblastic phenotype, reflected by the up-regulation of interleukin-6, interleukin-1ß, bone sialoprotein, osteoprotegerin, receptor activator of nuclear factor kappa B, bone morphogenic protein 2, and muscle segment homeobox 2, the production of osteocalcin, and the formation of calcium deposits. CONCLUSIONS: The acquisition of an osteoblastic phenotype in VICs that come into contact with the senescent RBCs of intraleaflet hematomas may play a critical role in the initiation of calcium deposition into the fibrosa of human aortic valves.
Assuntos
Estenose da Valva Aórtica/diagnóstico , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Calcinose/diagnóstico , Cálcio/metabolismo , Ferro/metabolismo , Idoso , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/metabolismo , Calcinose/metabolismo , Células Cultivadas , Progressão da Doença , Endotélio Vascular/metabolismo , Endotélio Vascular/ultraestrutura , Feminino , Humanos , Masculino , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência , Pessoa de Meia-Idade , FenótipoRESUMO
BACKGROUND: Aortic stenosis (AS) is an active disease, but the determinants of AS progression remain largely unknown. Low levels of Fetuin-A, a powerful inhibitor of ectopic calcification, have been linked to ectopic calcium tissue deposition but its role in AS progression has not been clearly evaluated. METHODS: In our ongoing prospective cohort (COFRASA/GENERAC), serum Fetuin-A level was measured at baseline and AS severity was evaluated at baseline and yearly thereafter using echocardiography (mean pressure gradient (MPG)) and computed tomography (degree of aortic valve calcification (AVC)). Annual progression was calculated as [(final measurement-baseline measurement)/follow-up duration] for both MPG and AVC measurements. RESULTS: We enrolled 296 patients (74⯱â¯10â¯years,73% men); mean follow-up duration was 3.0⯱â¯1.7â¯years. No correlation was found between baseline serum Fetuin-A (0.55⯱â¯0.15â¯g/L) and baseline AS severity (râ¯=â¯0.25, pâ¯=â¯0.87 for MPG; râ¯=â¯0.06, pâ¯=â¯0.36 for AVC). More importantly, there was no correlation between baseline serum Fetuin-A level and AS progression either assessed using MPG or AVC (both râ¯=â¯0.01, pâ¯=â¯0.82). In bivariate analysis, after adjustment for age, gender, baseline AS severity, or valve anatomy, Fetuin-A was not associated with AS progression (all pâ¯>â¯0.20). The absence of link with AS progression was further confirmed by the absence of link betwen serum Fetuin-A and the occurrence of AS-related events (pâ¯=â¯0.17). CONCLUSIONS: In a large prospective cohort of AS patients, serum Fetuin-A was not associated to hemodynamic or anatomic AS progression. Despite its capacity to inhibit ectopic calcium deposition, Fetuin-A serum level seemed to have minor influence on AS progression.
Assuntos
Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Calcinose/sangue , Calcinose/diagnóstico por imagem , Progressão da Doença , alfa-2-Glicoproteína-HS/metabolismo , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Biomarcadores/sangue , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Background: Ascending aorta (AA) dilatation is common in aortic valve stenosis (AS) but data regarding AA progression, its determinants and impact of valve anatomy [bicuspid (BAV), or tricuspid (TAV)] are scarce. Methods and Results: Asymptomatic AS patients enrolled in a prospective cohort (COFRASA/GENERAC) with at least 2 years of follow-up were considered in the present analysis. A transthoracic echocardiography (TTE) and a computed tomography (CT) scan were performed at inclusion and yearly thereafter. We enrolled 195 patients [mean gradient 22 ± 11 mmHg, 42 BAV patients (22%)]. Mean aorta diameters assessed using TTE were 35 ± 4 and 36 ± 5 mm at the sinuses of Valsalva and tubular level, respectively. Ascending aorta diameter was >40 mm in 29% of patients (24% in TAV vs. 52% in BAV, P < 0.01). Determinants of AA diameters were age, sex, BSA, and BAV, but not AS severity. After a mean follow-up of 3.8 ± 1.5years, AA enlargement rate assessed using TTE was +0.18 ± 0.34 mm/year and +0.36 ± 0.54 mm/year at the Valsalva and tubular level, respectively. Determinants of the progression of AA size were smaller AA diameter (P < 0.01) but not baseline AS severity or valve anatomy (all P > 0.05). Only four patients presented an AA progression ≥2 mm/year. Correlations between TTE and CT scan were excellent (all r >0.74) and similar results were obtained using CT. During follow-up, two BAV patients underwent a combined AA surgery; no surgery was primarily performed for AA aneurysm and no dissection was observed. Conclusion: In this prospective cohort of AS patients determinants of AA diameters were age, sex, BSA, and valve anatomy but not AS severity. AA progression rates were low and not influenced by AS severity or valve anatomy.
Assuntos
Aorta/patologia , Estenose da Valva Aórtica/diagnóstico por imagem , Doenças Assintomáticas/epidemiologia , Ecocardiografia/métodos , Tomografia Computadorizada por Raios X/métodos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aorta/diagnóstico por imagem , Estenose da Valva Aórtica/epidemiologia , Estenose da Valva Aórtica/patologia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Valva Mitral/diagnóstico por imagem , Valva Mitral/patologia , Prognóstico , Estudos Prospectivos , Medição de Risco , Sensibilidade e Especificidade , Fatores Sexuais , Valva Tricúspide/diagnóstico por imagem , Valva Tricúspide/patologiaRESUMO
OBJECTIVES: This study sought to evaluate the prognostic value of mean pressure gradient (MPG) increase and peak systolic pulmonary artery pressure (SPAP) measured during exercise stress echocardiography in asymptomatic patients with aortic stenosis (AS). BACKGROUND: Exercise testing is recommended in asymptomatic AS patients, but the additional value of exercise-stress echocardiography, especially the prognostic value of MPG increase and peak SPAP, is still debated. METHODS: We enrolled all consecutive patients with pure, isolated, asymptomatic AS and preserved ejection fraction ≥50% and normal SPAP (<50 mm Hg) who underwent symptom-limited exercise echocardiography at our institution. Occurrence of AS-related events (symptoms or congestive heart failure) or occurrence of aortic valve replacement was recorded. RESULTS: We enrolled 148 patients (66 ± 15 years of age; 74% males; MPG: 47 ± 13 mm Hg; SPAP: 34 ± 6 mm Hg). No complications were observed. Thirty-six patients (24%) had an abnormal exercise test result (occurrence of symptoms, fall in blood pressure, and/or ST-segment depression) and were referred for surgery. Among the 112 patients with a normal exercise test result, 38 patients (34%) had abnormal exercise echocardiography scores (MPG increase >20 mm Hg and/or SPAP at peak exercise >60 mm Hg). These 112 patients were managed conservatively. During a mean follow-up of 14 ± 8 months, an AS-related event occurred in 30 patients, and 25 patients underwent surgery. Neither MPG increase >20 mm Hg nor peak SPAP >60 mm Hg was predictive of occurrence of AS-related events or aortic valve replacement (all p > 0.20). In contrast, baseline AS severity was an important prognostic factor (all p < 0.01). CONCLUSIONS: In this observational study including 148 patients with asymptomatic AS, we confirmed and extended the importance of exercise testing for unveiling functional limitation. More importantly, neither the increase in MPG nor in SPAP at peak exercise was predictive of outcome. Our results do not support the use of these parameters in risk-stratification and clinical management of asymptomatic AS patients.
Assuntos
Estenose da Valva Aórtica/diagnóstico por imagem , Valva Aórtica/diagnóstico por imagem , Ecocardiografia sob Estresse/métodos , Teste de Esforço , Hemodinâmica , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/fisiopatologia , Estenose da Valva Aórtica/terapia , Pressão Arterial , Doenças Assintomáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/fisiopatologia , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Determinants of the progression of aortic stenosis (AS) remained unclear. Metabolic syndrome (MetS) and diabetes are suspected to play an active role but literature is scarce and results conflicting. We sought to assess their impact in an ongoing prospective cohort of asymptomatic patients with at least mild AS. METHODS: We enrolled 203 patients (73±9years, 75% men) with at least 2years of follow-up. Risk-factors assessment was performed at baseline. Annual progression was calculated as [(final-baseline measurements)/follow-up duration] for both mean pressure gradient (MPG) and degree of aortic valve calcification (AVC) measurements. RESULTS: Ninety-nine patients (49%) had MetS and 50 (25%) had diabetes (including 39 with MetS). After a mean follow-up of 3.2±1.2years, AS progression was not different between patients with and without MetS either using MPG (+3±3 vs. +4±4mmHg/year, p=0.25) or AVC (+211±231 vs. +225±222AU/year, p=0.75). Same results were obtained for patients with diabetes (3±3 vs. 4±4mmHg/year p=0.53, 187±140 vs. 229±248AU/year p=0.99). MetS had no impact on AS progression in all tested subgroups based on age, statin prescription, valve anatomy and AS severity (all p≥0.10). CONCLUSION: In our prospective cohort of AS patients, we found no impact of MetS or diabetes on AS progression. Although MetS and diabetes should be actively treated, no impact on AS progression should be expected. Our results support the theory that if cardiovascular risk-factors may play a role at the early phase of AS disease they have no or limited influence on AS progression.
Assuntos
Estenose da Valva Aórtica/diagnóstico por imagem , Valva Aórtica/patologia , Calcinose/diagnóstico por imagem , Diabetes Mellitus/diagnóstico por imagem , Progressão da Doença , Síndrome Metabólica/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/epidemiologia , Calcinose/epidemiologia , Estudos de Coortes , Diabetes Mellitus/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Estudos ProspectivosAssuntos
Estenose da Valva Aórtica/fisiopatologia , Valva Aórtica/patologia , Valva Aórtica/fisiopatologia , Calcinose/fisiopatologia , Disparidades nos Níveis de Saúde , Hemodinâmica , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/diagnóstico por imagem , Calcinose/diagnóstico por imagem , Progressão da Doença , Ecocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada Multidetectores , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
OBJECTIVE: Myocardial fibrosis has been proposed as an outcome predictor in asymptomatic patients with severe aortic stenosis (AS) that may lead to consider prophylactic surgery. It can be detected using MRI but its widespread use is limited and development of substitute biomarkers is highly desirable. We analysed the determinants and prognostic value of galectin-3, one promising biomarker linked to myocardial fibrosis. METHODS: Patients with at least mild degenerative AS enrolled between 2006 and 2013 in two ongoing studies, COFRASA/GENERAC (COhorte Française de Rétrécissement Aortique du Sujet Agé/GENEtique du Rétrécissement Aortique), aiming at assessing the determinants of AS occurrence and progression, constituted our population. RESULTS: We prospectively enrolled 583 patients. The mean galectin-3 value was 14.3±5.6â ng/mL. There was no association between galectin-3 and functional status (p=0.55) or AS severity (p=0.58). Independent determinants of galectin-3 were age (p=0.0008), female gender (p=0.04), hypertension (p=0.002), diabetes (p=0.02), reduced left ventricular ejection fraction (p=0.01), diastolic dysfunction (E/e', p=0.02) and creatinine clearance (p<0.0001). Among 330 asymptomatic patients at baseline, galectin-3 was neither predictive of outcome in univariate analysis (p=0.73), nor after adjustment for age, gender, rhythm, creatinine clearance and AS severity (p=0.66). CONCLUSIONS: In a prospective cohort of patients with a wide range of AS severity, galectin-3 was not associated with AS severity or functional status. Main determinants of galectin-3 were age, hypertension and renal function. Galectin-3 did not provide prognostic information on the occurrence of AS-related events. Our results do not support the use of galectin-3 in the decision-making process of asymptomatic patients with AS. TRIAL REGISTRATION NUMBER: COFRASA NCT00338676 and GENERAC CT00647088.
Assuntos
Estenose da Valva Aórtica/sangue , Galectina 3/sangue , Miocárdio/metabolismo , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/etiologia , Estenose da Valva Aórtica/fisiopatologia , Doenças Assintomáticas , Biomarcadores/sangue , Proteínas Sanguíneas , Distribuição de Qui-Quadrado , Progressão da Doença , Intervalo Livre de Doença , Ecocardiografia Doppler , Feminino , Fibrose , França , Galectinas , Humanos , Estimativa de Kaplan-Meier , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Miocárdio/patologia , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Função Ventricular EsquerdaRESUMO
BACKGROUND: Aortic valve stenosis (AS) is a progressive disease, but the impact of baseline AS haemodynamic or anatomic severity on AS progression remains unclear. METHODS: In 149 patients (104 mild AS, 36 moderate AS and 9 severe AS) enrolled in 2 ongoing prospective cohorts (COFRASA/GENERAC), we evaluated AS haemodynamic severity at baseline and yearly, thereafter, using echocardiography (mean pressure gradient (MPG)) and AS anatomic severity using CT (degree of aortic valve calcification (AVC)). RESULTS: After a mean follow-up of 2.9±1.0 years, mean MGP increased from 22±11 to 30±16 mm Hg (+3±3 mm Hg/year), and mean AVC from 1108±891 to 1640±1251 AU (arbitrary units) (+188±176 AU/year). Progression of AS was strongly related to baseline haemodynamic severity (+2±3 mm Hg/year in mild AS, +4±3 mm Hg/year in moderate AS and +5±5 mm Hg/year in severe AS (p=0.01)), and baseline haemodynamic severity was an independent predictor of haemodynamic progression (p=0.0003). Annualised haemodynamic and anatomic progression rates were significantly correlated (r=0.55, p<0.0001), but AVC progression rate was also significantly associated with baseline haemodynamic severity (+141±133 AU/year in mild AS, +279±189 AU/year in moderate AS and +361±293â AU/year in severe AS, p<0.0001), and both baseline MPG and baseline AVC were independent determinants of AVC progression (p<0.0001). CONCLUSIONS: AS progressed faster with increasing haemodynamic or anatomic severity. Our results suggest that a medical strategy aimed at preventing AVC progression may be useful in all subsets of patients with AS including those with severe AS and support the recommended closer follow-up of patients with AS as AS severity increases. CLINICAL TRIAL REGISTRATION: COFRASA (clinicalTrial.gov number NCT 00338676) and GENERAC (clinicalTrial.gov number NCT00647088).