RESUMEN
BACKGROUND AND PURPOSE: We aimed to assess the association between covert atherosclerosis, arterial stiffness, and early-onset cryptogenic ischemic stroke (CIS) in a prospective case-control study. METHODS: We enrolled 123 young CIS patients (median age 41 years; 42% women) and 123 age- and sex-matched controls. Carotid intima-media thickness (CIMT), Augmentation Index (AIx), central pulse wave velocity (PWV), and subendocardial viability ratio (SEVR) were compared between patients and controls. Conditional logistic regression was used adjusting for age, systolic blood pressure, diastolic blood pressure, current smoking, total cholesterol/high-density lipoprotein cholesterol (Total-C/HDL-C) ratio, and glycated albumin to assess the independent association between CIMT, arterial stiffness and CIS. RESULTS: Patients with higher CIMT and PWV were older, more often men and they had more frequently well-documented risk factors, lower HDL and higher Total-C/HDL-C ratio compared to other tertiles. In univariate comparisons, we found no differences between patients and controls regarding CIMT, AIx, or PWV. In the entire cohort, patients had a significantly lower SEVR compared to controls (146.3%, interquartile range [IQR] 125.7-170.3 vs. 158.0%, IQR 141.3-181.0, P=0.010). SEVR was lower also in women compared to their controls (132.0%, IQR 119.4-156.1 vs. 158.7%, IQR 142.0-182.8, P=0.001) but no significant difference appeared between male patients and male controls. However, after adjusting for comorbidities and laboratory values these significant differences were lost (odds ratio [OR] 1.52, 95% confidence interval [CI] 0.47-4.91) in the entire cohort and OR 3.89, 95% CI 0.30-50.80 in women). CONCLUSIONS: Higher CIMT and PWV were associated to higher age, male sex, and several well-documented cardiovascular risk factors. However, in this study we could not prove that either covert atherosclerosis or arterial stiffness contribute to pathogenesis of early-onset CIS.
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Aterosclerosis , Accidente Cerebrovascular Isquémico , Rigidez Vascular , Adulto , Envejecimiento , Biomarcadores , Grosor Intima-Media Carotídeo , Estudios de Casos y Controles , HDL-Colesterol , Femenino , Humanos , Masculino , Análisis de la Onda del Pulso , Factores de Riesgo , Rigidez Vascular/fisiologíaRESUMEN
BACKGROUND: Aortic valve stenosis (AS) is the most prevalent valvular disease in the developed countries. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) is an emerging imaging technique, which has been suggested to improve the evaluation of AS severity compared to two-dimensional (2D) flow and transthoracic echocardiography (TTE). We investigated the reliability of CMR 2D flow and 4D flow techniques in measuring aortic transvalvular peak systolic flow in patients with severe AS. METHODS: We prospectively recruited 90 patients referred for aortic valve replacement due to severe AS (73.3 ± 11.3 years, aortic valve area 0.7 ± 0.1 cm2, and 54/36 tricuspid/bicuspid), and 10 non-valvular disease controls. All the patients underwent echocardiography and 2D flow and 4D flow CMR. Peak flow velocity measurements were compared using Wilcoxon signed rank sum test and Bland-Altman analysis. RESULTS: 4D flow underestimated peak flow velocity in the AS group when compared with TTE (bias - 1.1 m/s, limits of agreement ± 1.4 m/s) and 2D flow (bias - 1.2 m/s, limits of agreement ± 1.6 m/s). The differences between values obtained by TTE (median 4.3 m/s, range 2.7-6.1 m/s) and 2D flow (median 4.5 m/s, range 2.9-6.5 m/s) compared to 4D flow (median 3.1 m/s, range 1.7-5.1 m/s) were significant (p < 0.001). The difference between 2D flow and TTE were insignificant (bias 0.07 m/s, limits of agreement ± 1.5 m/s). In non-valvular disease controls, peak flow velocity was measured higher by 4D flow than 2D flow (1.4 m/s, 1.1-1.7 m/s and 1.3 m/s, 1.1-1.5 m/s, respectively; bias 0.2 m/s, limits of agreement ± 0.16 m/s). CONCLUSIONS: CMR 4D flow significantly underestimates systolic peak flow velocity in patients with severe AS. 2D flow, in turn, estimated the AS velocity accurately, with measured peak flow velocities comparable to TTE.
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Estenosis de la Válvula Aórtica , Ecocardiografía , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Humanos , Espectroscopía de Resonancia Magnética , Valor Predictivo de las Pruebas , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets.
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Epigénesis Genética , Epigenómica/métodos , Isquemia Miocárdica/metabolismo , ARN/metabolismo , Transcriptoma , Biomarcadores , Estudios de Casos y Controles , Humanos , Proyectos de InvestigaciónRESUMEN
: In experimental aortic stenosis (AS), blockade of the renin-angiotensin system attenuates AS-related left ventricular (LV) dysfunction and improves survival. We tested whether candesartan, an angiotensin II type 1 receptor blocker, favorably influences LV structure and function and improves exercise capacity in AS patients. Fifty-one patients with severe AS were randomized to receive candesartan (target dose 16 mg/d) or placebo. Eight patients discontinued treatment and the remaining 43 patients underwent echocardiography, walking test, and measurement of plasma N-terminal B-type natriuretic peptide (Nt-proBNP) before and after an average of 5-month treatment. No statistically significant changes in LV diameters, mass, or function were seen. The median 6-minute walking distance decreased from 390 to 368 m with candesartan (P = 0.003) and from 380 to 370 m with placebo (P = 0.523), reflecting natural progression of AS. Concomitantly, median Nt-proBNP increased from 319 to 414 ng/L with candesartan (P = 0.170) and from 413 to 561 ng/L with placebo (P = 0.035). No change with candesartan was statistically significantly different from the corresponding change with placebo. In conclusion, candesartan was well tolerated but had no favorable effects on the LV or effort tolerance. The benefits found in experimental AS of blocking the renin-angiotensin system could not be reproduced in patients with severe AS.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Bencimidazoles/uso terapéutico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Tetrazoles/uso terapéutico , Disfunción Ventricular Izquierda/tratamiento farmacológico , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos adversos , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/fisiopatología , Bencimidazoles/efectos adversos , Biomarcadores/sangre , Compuestos de Bifenilo , Progresión de la Enfermedad , Tolerancia al Ejercicio/efectos de los fármacos , Femenino , Finlandia , Humanos , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Recuperación de la Función , Índice de Severidad de la Enfermedad , Tetrazoles/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
Atrial fibrillation (AF) is common in patients with aortic stenosis (AS) and complicates the assessment of AS severity. The overlapping of symptoms in these 2 conditions may postpone valve replacement. This study aimed to evaluate the effect of AF on the severity assessment of AS and its impact on symptoms and quality of life (QoL). Patients with severe AS were prospectively recruited. Echocardiography, symptom questionnaires, and RAND-36 QoL assessment were performed preoperatively and 3 months postoperatively. The aortic valve calcium score (AVC) was measured using computed tomography. Of the 279 patients, 74 (26.5%) had AF. Patients with AF had lower mean gradients and 45.9% had a low-gradient phenotype, with a mean gradient <40 mm Hg, compared with 22.4% of those without AF (p <0.001). The AVC measurements revealed severe valve calcification equally in patients with or without AF (85.7% vs 87.7%, p = 0.78). Patients with AF were more symptomatic at baseline, with 50.0% versus 27.3% in New York Heart Association class III or higher (p <0.001), and after intervention. Patients with AF had more residual dyspnea (27.3% vs 12.0%, p = 0.007) and exercise intolerance (36.4% vs 17.0%, p = 0.002). The QoL improved significantly in both groups but was worse at baseline in patients with AF and remained impaired after intervention. In conclusion, low-gradient AS phenotype is overrepresented in patients with AF, but they have equally severe stenosis determined using AVC, despite the lower gradients. Patients with AF have more symptoms and worse QoL, but they improve significantly after intervention. In patients with AF, multimodality imaging is important in the assessment of AS severity.
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Estenosis de la Válvula Aórtica , Fibrilación Atrial , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico por imagen , Calidad de Vida , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/cirugía , Ecocardiografía , Válvula Aórtica/cirugía , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND & AIMS: Consumption of plant stanols and plant sterols decreases LDL cholesterol level and increases serum concentrations of plant stanols/sterols, but it is practically unexplored whether also their tissue concentrations increase. Thus, the aim of this study was to assess whether consuming plant stanols/sterols increases their concentrations in stenotic aortic valves and affect the valvular structure (collagen and elastin) or inflammation (macrophages and mast cells). METHODS: In a randomized, double-blind controlled intervention patients with severe aortic stenosis consumed margarine without (n = 11) or with 2 g of plant stanols (n = 12) or sterols (n = 13) until valve replacement surgery (2.6 months, on average). The effects of sitostanol and sitosterol on the expression and secretion of proinflammatory cytokines by cultured aortic valve myofibroblasts were also assessed. RESULTS: Control-related LDL-cholesterol was diminished by 16% (p < 0.05) by plant stanol and by 11% (NS) by plant sterol consumption, respectively. In the resected valves, cholesterol, plant stanol and sterol levels were similar in all groups. Consumed plant stanols or sterols had no effect on valvular structure or mast cell or macrophage numbers in valves. Incubation of cultured myofibroblasts derived from stenotic valves with sitostanol or sitosterol decreased mRNA expression of the monocyte chemotactic protein-1 (p < 0.05) and interleukin-1 beta (p < 0.05). CONCLUSIONS: In this study, plant stanol/sterol consumption did not affect cholesterol, plant stanol or sterol levels in stenotic aortic valves; neither did they influence the structure or the inflammatory status of the valves. However, these findings need to be confirmed in a larger-scale intervention. ClinicalTrials.govRegister #NCT00738933.
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Válvula Aórtica/efectos de los fármacos , Fitosteroles/administración & dosificación , Anciano , Anciano de 80 o más Años , Válvula Aórtica/patología , Válvula Aórtica/cirugía , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , LDL-Colesterol/sangre , Dieta , Método Doble Ciego , Femenino , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Margarina , Persona de Mediana Edad , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Fitosteroles/sangre , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sitoesteroles/administración & dosificación , Sitoesteroles/sangreRESUMEN
Calcific aortic valve disease (CAVD) is a progressive pathological condition with no effective pharmacological therapy. To identify novel molecular pathways as potential targets for pharmacotherapy, we studied microRNA (miRNA) profiles of heavily stenotic aortic valves (AS). One of the most upregulated miRNAs in AS valves compared to control valves was miR-125b (1.4-fold; P < 0.05). To identify CAVD-related changes in gene expression, DNA microarray analysis was performed, including an intermediate fibro(sclero)tic stage of the disease. This revealed changes especially in genes related to inflammation and immune response, including chemokine (C-C motif) ligand 3 (CCL3) and 4 (CCL4). CCL3 mRNA level was increased 3.9-fold (P < 0.05) when AS valves were compared to control valves, and a 2.5-fold increase (P < 0.05) in CCL4 gene expression was observed when fibro(sclero)tic valves were compared to control valves. Both CCL3 and CCL4 localized to macrophages by immunofluorescence. To identify chemokine-miRNA target pairs, data from miRNA target prediction databases were combined with valvular miRNA and mRNA expression profiles. MiR-125b was computationally predicted to target CCL4, as confirmed experimentally in cultured human THP-1 macrophages. Collectively, miR-125b and CCL4 appear to be involved in the progression of CAVD and may offer novel therapeutic and diagnostic strategies related to this disease.
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Estenosis de la Válvula Aórtica/metabolismo , Válvula Aórtica/metabolismo , Quimiocina CCL4/metabolismo , MicroARNs/metabolismo , Calcificación Vascular/metabolismo , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Quimiocina CCL4/genética , Humanos , MicroARNs/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/metabolismo , Regulación hacia ArribaRESUMEN
OBJECTIVE: To clarify the potential mechanisms by which oxidized low-density lipoprotein (oxLDL) could contribute to the progression of aortic valve stenosis (AVS). METHODS: We investigated a total of 46 stenotic and 20 control human aortic valves. The mRNA expression levels of scavenger receptor class A type 1 (SR-A1), CD36, Lectin-like oxidized LDL receptor-1 (LOX-1), and scavenger receptor class B type 1 (SR-B1) were studied using qPCR. Their cellular distribution in the valves was assessed by immunohistochemistry, and the potential effects of oxLDL were studied in cultured myofibroblasts isolated from the aortic valves. RESULTS: In AVS, the proinflammatory SR-A1 and the angiogenic LOX-1 were upregulated (p = 0.003 and p = 0.002), whereas the antiangiogenic CD36 was downregulated (p = 0.02). The expression of the atheroprotective SR-B1 remained unchanged. Immunohistochemistry revealed that SR-A1 was expressed by macrophages, whereas the expression of CD36 and LOX-1 was confined to myofibroblasts and endothelial cells in the diseased valves. In cultured valvular myofibroblasts, mast cell-derived components and TNF-α induced LOX-1 expression (p = 0.05 and p < 0.001), whereas oxLDL promoted the expression of proinflammatory cytokines. Furthermore, the expression of osteoprotegerin, an inhibitor of valvular calcification, decreased in response to oxLDL. Finally, myofibroblasts derived from stenotic valves accumulated more DiI-labeled oxLDL than myofibroblasts derived from macroscopically healthy valves (p = 0.035), so revealing enhanced foam cell-forming potential of myofibroblasts in the diseased valves. CONCLUSION: This study unveils the presence of SR-A1, CD36, and LOX-1 in aortic valves and suggests potential mechanisms by which they may contribute to the pathological angiogenesis, inflammation, calcification, and lipid accumulation in AVS.
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Estenosis de la Válvula Aórtica/fisiopatología , Antígenos CD36/metabolismo , Lipoproteínas LDL/metabolismo , Receptores Depuradores de Clase A/metabolismo , Receptores Depuradores de Clase E/metabolismo , Células Cultivadas , Progresión de la Enfermedad , Regulación hacia Abajo , Células Endoteliales/metabolismo , Humanos , Miofibroblastos/metabolismo , Osteoprotegerina/biosíntesis , Receptores Depuradores de Clase E/biosíntesis , Regulación hacia ArribaRESUMEN
In aortic stenosis plasma lipoprotein-derived lipids accumulate in aortic valves. Here, we first compared the lipid compositions of stenotic aortic valves and atherosclerotic plaque cores. Both pathological tissues were found to be enriched in cholesteryl linoleate, a marker of extracellularly accumulated lipoproteins. In addition, a large proportion of the phospholipids were found to contain arachidonic acid, the common precursor of a number of proinflammatory lipid mediators. Next, we isolated and characterized extracellular lipid particles from human stenotic and non-stenotic control valves, and compared them to plasma lipoproteins from the same subjects. The extracellular valvular lipid particles were isolated from 15 stenotic and 14 non-stenotic aortic valves. Significantly more apoB-100-containing lipid particles were found in the stenotic than in the non-stenotic valves. The majority of the lipid particles isolated from the non-stenotic valves had sizes (23±6.2 nm in diameter) similar to those of plasma low density lipoprotein (LDL) (22±1.5 nm), while the lipid particles from stenotic valves were not of uniform size, their sizes ranging from 18 to more than 500 nm. The lipid particles showed signs of oxidative modifications, and when compared to isolated plasma LDL particles, the lipid particles isolated from the stenotic valves had a higher sphingomyelin/phosphatidylcholine -ratio, and also higher contents of lysophosphatidylcholine and unesterified cholesterol. The findings of the present study reveal, for the first time, that in stenotic human aortic valves, infiltrated plasma lipoproteins have undergone oxidative and lipolytic modifications, and become fused and aggregated. The generated large lipid particles may contribute to the pathogenesis of human aortic stenosis.