RESUMEN
Multiple factors cause heart failure with preserved ejection fraction (HFpEF) and involve various systems. HFpEF prevalence is rapidly rising, and its prognosis remains poor after the first hospitalization. Adopting a more active lifestyle has been shown to provide beneficial clinical outcomes for patients with HFpEF. Using a two-hit HfpEF murine model, we studied cardiac reverse remodeling (RR) after stopping the causing stress and introducing voluntary exercise (VE). We checked in 2-mo-old male and female C57Bl6/J mice the heart's response to angiotensin II (ANG II; 1.5 mg/kg/day for 28 days) fed or not with a high-fat diet (HFD). Then, ANG II and/or the HFD were stopped, and VE was started for an additional 4 wk. ANG II and ANG II + HFD (metabolic-hypertensive stress, MHS) caused cardiac hypertrophy (CH) and myocardial fibrosis, left ventricular (LV) concentric remodeling, atrial enlargement, and reduced exercise capacity. HFD alone induced CH and LV concentric remodeling in female mice only. CH and LV concentric remodeling were reversed 4 wk after stopping ANG II, starting VE, and a low-fat diet. Left atrial enlargement and exercise capacity were improved but differed from controls. We performed bulk LV RNA sequencing and observed that MHS upregulated 58% of the differentially expressed genes (DEGs) compared with controls. In the RR group, compared with MHS animals, 60% of the DEGs were downregulated. In an HfpEF mouse model, we show that correcting hypertension, diet, and introducing exercise can lead to extensive cardiac reverse remodeling.NEW & NOTEWORTHY Using a two-hit murine model of heart failure with preserved ejection fraction (HfpEF), combining elevated blood pressure, obesity, and exercise intolerance in male and female animals, we showed that correction of hypertension, normalization of the diet, and introduction of voluntary exercise could help reverse the remodeling of the left ventricle and double exercise capacity. We also identify genes that escape normalization after myocardial recovery and differences between males' and females' responses to stress and recovery.
Asunto(s)
Insuficiencia Cardíaca , Hipertensión , Humanos , Masculino , Femenino , Ratones , Animales , Modelos Animales de Enfermedad , Volumen Sistólico/fisiología , Miocardio , Remodelación Ventricular/fisiología , Función Ventricular Izquierda/fisiologíaRESUMEN
Age, hypertension, and the female sex are among the risk factors in the development of heart failure with preserved ejection fraction. We studied by standard and speckle-tracking echocardiography (STE), the response of the left ventricle (LV) to aging and angiotensin II continuous infusion (ANG II; 1.5 mg/kg/day for 28 days) in 2- and 12-mo-old male and female C57Bl6/J mice. We also investigated the effects of the loss of sex steroids by gonadectomy (GDX). To do so, we used STE data from 48 points or regions of interest (ROIs) around the LV endocardium from B-mode images and generated profiles of maximal strain, strain rate (SR), and reverse SR for each experimental group of mice. In young mice, LV strain, strain rate (SR), and reverse SR profile levels were higher in females than in males. Aging was characterized by concentric LV remodeling and a decrease of strain, SR, and reverse SR. GDX at 6 wk of age slowed normal cardiac growth in male mice. In females, GDX reduced LV strain, SR, and reverse SR but did not influence cardiac growth. ANG II caused similar levels of hypertrophy in young and older mice. In young mice, ANG II had little effect on STE parameters, whereas in older animals, strain, SR, and reverse SR were reduced, mainly for the LV posterior wall. In older GDX mice, hypertrophic response to ANG II was decreased compared with intact animals. Generating detailed STE profile for the LV wall can help detect differences linked to sex, age, or a stressor better than global strain measurements.NEW & NOTEWORTHY We propose a new method for the study of regional strain data by analyzing individually the software-generated 48 regions of interest (ROI) from an LV wall tracing in B-mode. This helps obtain a more comprehensive profile of strain data. Using these new tools, we studied in mice how sex, sex hormones, age, or a pathological stress influenced strain parameters. We show that for similar cardiac hypertrophy, regional strain shows important differences related to sex, sex hormones, and age.
Asunto(s)
Angiotensina II , Ventrículos Cardíacos , Animales , Femenino , Hormonas Esteroides Gonadales , Ventrículos Cardíacos/diagnóstico por imagen , Masculino , Ratones , Ratones Endogámicos C57BL , Esteroides , Función Ventricular Izquierda/fisiologíaRESUMEN
BACKGROUND: Aortic valve regurgitation (AR) results in left ventricle (LV) volume overload (VO) leading to its dilation and hypertrophy (H). We study a rat model of severe AR induced by puncturing one or two leaflets using a catheter. Most of our studies were conducted in male animals. Recently, we started investigating if sex dimorphism existed in the AR rat model. We observed that AR females developed as much LVH as males but morphological remodeling differences were present. A head-to-head comparison of LV morphological and functional changes had never been performed in AR males (M) and females (F) using the latest modalities in cardiac imaging by echocardiography. METHODS: We performed a longitudinal study to evaluate the development of LV hypertrophy caused by chronic AR in male and female rats over 6 months. Sham-operated (sham) animals were used as controls. RESULTS: LV diastolic volumes (EDV) increased more over 6 months in sham males than in females (38% vs. 23% for EDV, both p < 0.01). AR resulted in significant LV dilation for both sexes (54% vs. 51% increase in EDV) vs. baseline values. Since normal cardiac growth was less in females, dilation from AR was relatively more important for them (88% (M) vs. 157% (F) increase in EDV over sham). AR caused LV wall thickening in both males and females. It happened sooner for AR females and was more important than in males (25% (M) vs. 56% (F) increase in septum thickness at 2 months and 10% (M) vs. 30% (F) at 6 months). We then evaluated if AR was associated with changes in LV strain using speckle-tracking 2D echocardiography. Global longitudinal strain remained similar between AR and sham animals. Circumferential strain was negatively modulated by AR but only in females and early after VO induction (13% (M) vs. 26% (F)). CONCLUSION: AR resulted in more LV dilation and quicker wall thickening in female AR rats compared to males. Global circumferential strain was negatively modulated in AR females but not in males. AR also seemed to lead to a more spherical LV shape in females whereas; it kept mostly an ellipsoid shape in males. This can influence validity of mass estimation of the dilated LV in females by echocardiography.
Asunto(s)
Insuficiencia de la Válvula Aórtica/complicaciones , Hipertrofia Ventricular Izquierda/etiología , Función Ventricular Izquierda , Remodelación Ventricular , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/fisiopatología , Modelos Animales de Enfermedad , Femenino , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Ratas Wistar , Índice de Severidad de la Enfermedad , Caracteres Sexuales , Factores Sexuales , Factores de TiempoRESUMEN
BACKGROUND AND AIM OF THE STUDY: Mitral leaflet enlargement in patients with chronic aortic regurgitation (AR) has been identified as an adaptive mechanism potentially able to prevent functional mitral regurgitation (FMR) in response to left ventricular (LV) dilatation. The timing of valve enlargement is not known, and the related mechanisms are largely unexplored. METHODS: AR was induced in 58 rats, and another 54 were used as sham controls. Animals were euthanized at different time points after AR creation (48 h, one week, and three months), and AR severity, FMR and LV dilatation were assessed using echocardiography. Mitral valves were harvested to document the reactivation of embryonic growth pathways. RESULTS: AR animals had increased LV dimensions and mitral annulus size. No animal developed FMR. No change in leaflet length or thickness was seen at 48 h; however, anterior mitral leaflets were longer and thicker in AR animals at one week and three months. Molecular changes were present early (at 48 h and at one week), with positive staining for transforming growth factor-b1 (TGF-b1), Alpha-smooth muscle actin (α-SMA) and matrix metalloproteinase-2 (MMP-2), which suggested active matrix remodeling. Increased gene expression for collagen 1, TGF-ß1, α-SMA and MMP-2 was found in the mitral valve at 48 h and at one week, but after three months their expression had returned to normal. CONCLUSIONS: This model of AR induces active expansion and thickening of the mitral leaflets. Growth signals are expressed acutely, but not at three months, which suggests that most of this enlargement occurs at an early stage. The stimulation of valvular growth could represent a new strategy for the prevention of FMR.
Asunto(s)
Insuficiencia de la Válvula Aórtica/patología , Proliferación Celular , Matriz Extracelular/patología , Válvula Mitral/patología , Actinas/genética , Actinas/metabolismo , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/metabolismo , Insuficiencia de la Válvula Aórtica/fisiopatología , Modelos Animales de Enfermedad , Ecocardiografía Doppler , Matriz Extracelular/metabolismo , Hipertrofia Ventricular Izquierda/patología , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/metabolismo , Válvula Mitral/fisiopatología , Ratas Wistar , Factores de Tiempo , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Regulación hacia Arriba , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
BACKGROUND: The composition of a diet can influence myocardial metabolism and development of left ventricular hypertrophy (LVH). The impact of a high-fat diet in chronic left ventricular volume overload (VO) causing eccentric LVH is unknown. This study examined the effects of chronic ingestion of a high-fat diet in rats with chronic VO caused by severe aortic valve regurgitation (AR) on LVH, function and on myocardial energetics and survival. METHODS: Male Wistar rats were divided in four groups: Shams on control or high-fat (HF) diet (15 rats/group) and AR rats fed with the same diets (ARC (n = 56) and ARHF (n = 32)). HF diet was started one week before AR induction and the protocol was stopped 30 weeks later. RESULTS: As expected, AR caused significant LV dilation and hypertrophy and this was exacerbated in the ARHF group. Moreover, survival in the ARHF group was significantly decreased compared the ARC group. Although the sham animals on HF also developed significant obesity compared to those on control diet, this was not associated with heart hypertrophy. The HF diet in AR rats partially countered the expected shift in myocardial energy substrate preference usually observed in heart hypertrophy (from fatty acids towards glucose). Systolic function was decreased in AR rats but HF diet had no impact on this parameter. The response to HF diet of different fatty acid oxidation markers as well as the increase in glucose transporter-4 translocation to the plasma membrane compared to ARC was blunted in AR animals compared to those on control diet. CONCLUSIONS: HF diet for 30 weeks decreased survival of AR rats and worsened eccentric hypertrophy without affecting systolic function. The expected adaptation of myocardial energetics to volume-overload left ventricle hypertrophy in AR animals seemed to be impaired by the high-fat diet suggesting less metabolic flexibility.
Asunto(s)
Insuficiencia de la Válvula Aórtica/complicaciones , Dieta Alta en Grasa/efectos adversos , Hipertrofia Ventricular Izquierda/etiología , Obesidad/complicaciones , Adaptación Fisiológica , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico , Insuficiencia de la Válvula Aórtica/metabolismo , Insuficiencia de la Válvula Aórtica/fisiopatología , Modelos Animales de Enfermedad , Metabolismo Energético , Ácidos Grasos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Glucosa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Miocardio/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Obesidad/metabolismo , Obesidad/fisiopatología , Oxidación-Reducción , Ratas Wistar , Factores de Riesgo , Factores de Tiempo , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Patients with chronic aortic valve regurgitation (AR) causing left ventricular (LV) volume overload can remain asymptomatic for many years despite having a severely dilated heart. The sudden development of heart failure is not well understood but alterations of myocardial energy metabolism may be contributive. We studied the evolution of LV energy metabolism in experimental AR. METHODS: LV glucose utilization was evaluated in vivo by positron emission tomography (microPET) scanning of 6-month AR rats. Sham-operated or AR rats (n = 10-30 animals/group) were evaluated 3, 6 or 9 months post-surgery. We also tested treatment intervention in order to evaluate their impact on metabolism. AR rats (20 animals) were trained on a treadmill 5 times a week for 9 months and another group of rats received a beta-blockade treatment (carvedilol) for 6 months. RESULTS: MicroPET revealed an abnormal increase in glucose consumption in the LV free wall of AR rats at 6 months. On the other hand, fatty acid beta-oxidation was significantly reduced compared to sham control rats 6 months post AR induction. A significant decrease in citrate synthase and complex 1 activity suggested that mitochondrial oxidative phosphorylation was also affected maybe as soon as 3 months post-AR.Moderate intensity endurance training starting 2 weeks post-AR was able to partially normalize the activity of various myocardial enzymes implicated in energy metabolism. The same was true for the AR rats treated with carvedilol (30 mg/kg/d). Responses to these interventions were different at the level of gene expression. We measured mRNA levels of a number of genes implicated in the transport of energy substrates and we observed that training did not reverse the general down-regulation of these genes in AR rats whereas carvedilol normalized the expression of most of them. CONCLUSION: This study shows that myocardial energy metabolism remodeling taking place in the dilated left ventricle submitted to severe volume overload from AR can be partially avoided by exercise or beta-blockade in rats.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/farmacología , Insuficiencia de la Válvula Aórtica/metabolismo , Metabolismo Energético/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Condicionamiento Físico Animal , Resistencia Física , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Modelos Animales de Enfermedad , Regulación hacia Abajo , Glucosa/metabolismo , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/efectos de los fármacos , Masculino , Miocardio/metabolismo , Ratas Wistar , UltrasonografíaRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterised by multiple risk factors touching various organs outside the heart. Using a murine HFpEF model, we studied cardiac reverse remodelling (RR) after stopping the causing metabolic-hypertensive stress (MHS; Angiotensin II [AngII] and a high-fat diet [HFD]) after 28 days and introducing voluntary exercise (VE) for four more weeks. We measured the effects of MHS and RR on the plasma and myocardial microRNA (miR) profile (miRNome) to characterise better cardiac and non-cardiac responses to HFpEF-inducing risk factors and their reversibility. AngII alone, the HFD or the MHS caused cardiac hypertrophy (CH), left ventricular (LV) concentric remodelling and left atrial enlargement in females. Only AngII and the MHS, but not HFD, did in males. After RR, CH, LV concentric remodelling and atrial enlargement were normalised. Among the 25 most abundant circulating miRs, 10 were modulated by MHS. Plasma miRNomes from AngII, HFD or MHS mice shared 31 common significantly modulated miRs (24 upregulated and 7 downregulated), suggesting that the response of organs producing the bulk of those circulating miRs was similar even for seemingly different stress. In the LV, 19 out of 25 most expressed miRs were modulated. RR restored normality for the plasma miRNome but not for the LV miRNome, which remained mostly unchanged. Our results suggest that abnormalities persist in the myocardium of the HFpEF mice and that the normalisation of circulatory markers may be falsely reassuring after recovery.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca , MicroARNs , Miocardio , Volumen Sistólico , Remodelación Ventricular , Animales , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/metabolismo , Ratones , MicroARNs/genética , MicroARNs/sangre , MicroARNs/metabolismo , Masculino , Miocardio/metabolismo , Miocardio/patología , Femenino , Angiotensina II/sangre , Angiotensina II/metabolismo , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversosRESUMEN
We propose a new mouse (C57Bl6/J) model combining several features of heart failure with preserved ejection fraction encountered in older women, including hypertension from Angiotensin II infusion (AngII), menopause, and advanced age. To mimic menopause, we delayed ovariectomy (Ovx) at 12 months of age. We also studied the effects of AngII infusion for 28 days in younger animals and the impact of losing gonadal steroids earlier in life. We observed that AngII effects on heart morphology were different in younger and adult mice (3- and 12-month-old; 20 and 19% increase in heart weight. P < 0.01 for both) than in older animals (24-month-old; 6%; not significant). Ovariectomy at 12 months restored the hypertrophic response to AngII in elderly females (23%, p = 0.0001). We performed a bulk RNA sequencing study of the left ventricle (LV) and left atrial gene expression in elderly animals, controls, and Ovx. AngII modulated (|Log2 fold change| ≥ 1) the LV expression of 170 genes in control females and 179 in Ovx ones, 64 being shared. In the left atrium, AngII modulated 235 genes in control females and 453 in Ovx, 140 shared. We observed many upregulated genes associated with the extracellular matrix regulation in both heart chambers. Many of these upregulated genes were shared between the ventricle and the atrium as well as in control and Ovx animals, namely for the most expressed Ankrd1, Nppb, Col3a1, Col1a1, Ctgf Col8a1, and Cilp. Several circadian clock LV genes were modulated differently by AngII between control and Ovx females (Clock, Arntl, Per2, Cry2, and Ciart). In conclusion, sex hormones, even in elderly female mice, modulate the heart's hypertrophic response to AngII. Our study identifies potential new markers of hypertensive disease in aging female mice and possible disturbances of their cardiac circadian clock.
Asunto(s)
Angiotensina II , Modelos Animales de Enfermedad , Hipertensión , Ratones Endogámicos C57BL , Ovariectomía , Animales , Femenino , Angiotensina II/farmacología , Ratones , Hipertensión/fisiopatología , Envejecimiento/fisiología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Menopausia , Humanos , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/efectos de los fármacos , Atrios Cardíacos/patología , Colágeno Tipo IIIRESUMEN
After menopause, the incidence of cardiovascular disease rapidly rises in women. The disappearing protection provided by sex steroids is a consequence of the development of many risk factors. Preclinical studies are necessary to understand better the effects of ovarian hormones loss cardiac aging. To mimic menopause in mice and study its consequences, we delayed ovariectomy at 12 months and followed animals for 12 months. Using RNA sequencing, we investigated changes in the myocardial exome with aging. In addition, with four-core genotypes (FCG) transgenic mice, we studied sex chromosome effects on cardiac aging. Heart weight increased from 3 to 24 months (males + 35%, females + 29%). In males, 75% of this increase had occurred at 12 months; in females, only 30%. Gonadectomy of mice at 12 months blocked cardiac hypertrophy in both sexes during the second year of life. The dosage of the X chromosomes did not influence cardiac growth in young and older mice. We performed an RNA sequencing study in young and old mice. We identified new highly expressed genes modulated during aging (Bdh, Myot, Cpxm2, and Slc38a1). The myocardial exome in older animals displayed few differences related to the animal's sex or the presence or absence of sex steroids for a year. We show that the morphological evolution of the heart depends on the biological sex via gonadal sex hormone actions. The myocardial exome of old male and female mice is relatively similar. Our study emphasizes the need to consider sex steroid effects in studying cardiac aging.
Asunto(s)
Envejecimiento , Hormonas Esteroides Gonadales , Cromosomas Sexuales , Animales , Femenino , Masculino , Envejecimiento/genética , Ratones , Hormonas Esteroides Gonadales/metabolismo , Cromosomas Sexuales/genética , Ratones Transgénicos , Ovariectomía , Corazón , Miocardio/metabolismo , Miocardio/patología , Factores Sexuales , Cardiomegalia/genéticaRESUMEN
BACKGROUND: Thresholds of aortic valve calcification (AVC) to define hemodynamically moderate aortic stenosis (AS) from mild are lacking. We aimed to establish a novel grading classification of AVC as quantified by computed tomography and determine its prognostic value. METHODS AND RESULTS: This study included 915 patients with at least mild AS (mean age 70±12 years, 30% women) from a multicenter prospective registry. All patients underwent Doppler-echocardiography and noncontrast computed tomography within 3 months. Primary end point was the occurrence of all-cause death. Receiver operating characteristic curves analyses were used to determine the sensitivity and specificity of sex-specific thresholds of AVC to identify hemodynamically moderate AS. Optimal thresholds (ie, with best sensitivity/specificity) of AVC to distinguish moderate (aortic valve area 1.0-1.5 cm2 and mean gradient 20-39 mm Hg) from mild AS (aortic valve area >1.5 cm2 and mean gradient <20 mm Hg) were AVC ≥360 arbitrary units in women and ≥1037 arbitrary units in men. Based on the guidelines' thresholds for severe AS and the new thresholds in our study for moderate AS, 312 (34%) patients had mild, 253 (28%) moderate, and 350 (38%) severe AVC. During a mean follow-up of 5.6±3.9 years, 183 (27%) deaths occurred. In Cox multivariable models, AVC remained associated with an increased risk of death (adjusted hazard ratio per grade increase, 1.94 [95% CI, 1.53-2.56]; P<0.001). CONCLUSIONS: A novel grading classification of anatomic AS severity based on sex-specific thresholds of AVC provides significant prognostic value for predicting mortality. These findings support the complementarity of computed tomography-calcium scoring to Doppler-echocardiography to corroborate AS severity and enhance risk stratification in patients with AS.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Ecocardiografía Doppler , Sistema de Registros , Índice de Severidad de la Enfermedad , Humanos , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/mortalidad , Estenosis de la Válvula Aórtica/fisiopatología , Estenosis de la Válvula Aórtica/clasificación , Masculino , Femenino , Anciano , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/patología , Calcinosis/diagnóstico por imagen , Calcinosis/mortalidad , Medición de Riesgo/métodos , Anciano de 80 o más Años , Estudios Prospectivos , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos X , Curva ROC , HemodinámicaRESUMEN
BACKGROUND: Experimental studies revealed that renin-angiotensin system (RAS) could play a crucial role in the pathophysiology of aortic stenosis (AS). The objectives of this study were to examine (i) the impact of hypertension on AS progression and clinical events and (ii) the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs). MATERIALS AND METHODS: In this observational study, we retrospectively analysed clinical and Doppler echocardiographic data prospectively collected in 338 patients with AS. Patients were separated into four groups: patients without hypertension and not treated by RAS medication (Ctrl group), patients with hypertension but not treated by RAS medication (HTN group), patients treated with ACEIs, and patients treated with ARBs. AS progression rate was assessed by the annualized increase in peak aortic jet velocity. RESULTS: Compared with Ctrl group, patients in HTN group had faster stenosis progression (P = 0·01). Patients on ARBs had slower AS progression compared with Ctrl (trend P = 0·10) and HTN (P = 0·002) groups, whereas patients on ACEIs had similar progression rate compared with Ctrl group (P = NS) but lower compared with HTN group (P = 0·02). On multivariable analysis, compared with Ctrl group, HTN group was associated with faster AS progression rate (P = 0·002), whereas ARBs with slower progression (P = 0·0008). During a mean follow-up of 6·2 ± 2·4 years, HTN (hazard ratio [HR] = 2·45; P = 0·006) and ACEI (HR = 2·30; P = 0·01) groups were associated with a significant increase in all-cause mortality compared with Ctrl group, whereas ARB group (HR: 0·89; P = 0·80) not. In multivariable analysis, HTN and ACEI groups remained associated with increased mortality. CONCLUSIONS: Hypertension is associated with significantly faster stenosis progression and higher incidence of clinical events in patients with AS. ARBs but not ACEs were found to abolish the increased risk of mortality associated with hypertension.
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Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Estenosis de la Válvula Aórtica/etiología , Hipertensión/complicaciones , Factores de Edad , Anciano , Estenosis de la Válvula Aórtica/mortalidad , Estenosis de la Válvula Aórtica/prevención & control , Progresión de la Enfermedad , Ecocardiografía Doppler , Métodos Epidemiológicos , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/mortalidad , Masculino , Persona de Mediana Edad , Factores Sexuales , Resultado del Tratamiento , Calcificación Vascular/etiología , Calcificación Vascular/prevención & controlRESUMEN
BACKGROUND AND AIM OF THE STUDY: Aortic regurgitation (AR) is a disease for which there is currently no effective medical treatment. It has been shown previously in an experimental model of AR that the renin-angiotensin-aldosterone system (RAAS) plays a major role, and that medications blocking the RAAS are effective to protect against left ventricular (LV) hypertrophy and also help to maintain a normal systolic function. The role of aldosterone receptor blockers in this disease has never been evaluated. Thus, the effects were studied of the aldosterone receptor blocking agent spironolactone in a model of chronic AR in rats. METHODS: The effects of a six-month treatment with spironolactone were evaluated in adult Wistar rats with severe AR, compared to sham-operated and untreated AR animals. RESULTS: Spironolactone treatment decreased the total heart weight. In addition, the LV expression of atrial natriuretic peptide mRNA was decreased by spironolactone treatment, as was the expression of collagen 1 and LOX1 mRNAs. Left ventricular fibrosis was decreased by spironolactone treatment. CONCLUSION: Spironolactone protected against volume-overload cardiomyopathy in this model of aortic valve regurgitation. The predominant protective effect was a decrease in myocardial fibrosis.
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Insuficiencia de la Válvula Aórtica/tratamiento farmacológico , Cardiomegalia/tratamiento farmacológico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Espironolactona/farmacología , Animales , Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Insuficiencia de la Válvula Aórtica/fisiopatología , Presión Sanguínea/efectos de los fármacos , Cardiomegalia/diagnóstico por imagen , Cardiomegalia/fisiopatología , Enfermedad Crónica , Diástole/fisiología , Modelos Animales de Enfermedad , Ecocardiografía , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Presión Ventricular/fisiologíaRESUMEN
Background: Bicuspid aortic valve (BAV) is associated with a faster progression of aortic stenosis (AS). Whether the determinants of AS progression are the same or different in patients with BAV vs tricuspid aortic valve (TAV) is unknown. The aim of this study was to identify the factors associated with the progression of AS in patients with BAV vs patients with TAV. Methods: Patients with AS were prospectively recruited in the Metabolic Determinants of the Progression of Aortic Stenosis (PROGRESSA) study (ClinicalTrials.gov Identifier: NCT01679431). The haemodynamic progression rate of AS was assessed by the annualized progression rate of peak aortic jet velocity (Vpeak). Univariable and multivariable linear regression analyses were used to identify the factors associated with a faster progression of AS in patients with BAV vs patients with TAV. Results: There were 79 patients with BAV and 208 patients with TAV. The baseline severity of AS was similar between the 2 groups of patients as well as the annualized progression rate of AS. In patients with BAV, obesity (ß = 0.25, P = 0.04), diabetes (ß = 0.26, P = 0.02), and BAV with right-noncoronary cusp fusion (ß = 0.29, P = 0.01) were found to be independently associated with a faster progression of AS, whereas in patients with TAV, AS baseline severity (baseline Vpeak, ß = 0.14, P = 0.04) and chronic kidney disease (ß = 0.16, P = 0.02) were significantly associated with AS progression. Conclusion: Factors associated with progression rate of AS are different in BAV and TAV. The main factors associated with a faster progression of AS appear to be obesity, diabetes, right-noncoronary cusp fusion in patients with BAV vs chronic kidney disease in patients with TAV.
Contexte: La bicuspidie valvulaire aortique (BVA) est associée à une progression plus rapide de la sténose aortique (SA). On ignore toutefois si les facteurs en cause dans la progression de la SA sont les mêmes chez les patients qui présentent une BVA et chez ceux qui présentent une valve aortique tricuspide. Le but de cette étude était de déterminer les facteurs associés à la progression de la SA chez les patients présentant une BVA par rapport à ceux ayant une valve aortique tricuspide. Méthodologie: Des patients présentant une SA ont été recrutés dans l'étude PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis), une étude prospective sur les déterminants métaboliques de la progression de la SA (ClinicalTrials.gov : NCT01679431). Pour calculer le taux de progression hémodynamique de la SA, on a utilisé les mesures annualisées de la vélocité maximale du jet transaortique (Vmax). Des analyses de régression linéaire univariées et multivariées ont permis de mettre en évidence les facteurs associés à une progression plus rapide de la SA en présence d'une BVA par rapport à une valve aortique tricuspide. Résultats: Parmi les patients évalués, 79 présentaient une BVA et 208, une valve aortique tricuspide. La gravité de la SA au départ était comparable entre les deux groupes de patients, tout comme le taux de progression annualisé de la SA. Chez les patients avec BVA, l'obésité (ß = 0,25, P = 0,04), le diabète (ß = 0,26, P = 0,02) et la BVA avec fusion des feuillets coronaire droit et non coronaire (ß = 0,29, P = 0,01) ont été associés de manière indépendante à une progression plus rapide de la SA, tandis que chez les patients ayant une valve tricuspide, la gravité de la SA au départ (Vmax initiale, ß = 0,14, P = 0,04) et la présence d'une néphropathie chronique (ß = 0,16, P = 0,02) ont été significativement associées à une progression de la SA. Conclusion: Les facteurs associés au taux de progression de la SA sont différents selon qu'il y a ou non présence d'une BVA. Les principaux facteurs associés à une progression plus rapide de la SA semblent être l'obésité, le diabète et la fusion des feuillets coronaire droit et non coronaire pour la BVA, tandis que la néphropathie chronique serait le facteur aggravant chez les patients présentant une valve aortique tricuspide.
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BACKGROUND: Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR). OBJECTIVES: This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology. METHODS: Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals. RESULTS: Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals. CONCLUSIONS: Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR.
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Estenosis de la Válvula Aórtica , Calcinosis , Insuficiencia de la Válvula Mitral , Infarto del Miocardio , Animales , Válvula Aórtica , Células Cultivadas , Ciproheptadina/farmacología , Ciproheptadina/uso terapéutico , Fibrosis , Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/etiología , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Serotonina , Ovinos , Remodelación Ventricular/fisiologíaRESUMEN
The development of left ventricular (LV) hypertrophy (LVH) can be affected by diet manipulation. Concentric LVH resulting from pressure overload can be worsened by feeding rats with a high-fructose diet. Eccentric LVH is a different type of hypertrophy and is associated with volume overload (VO) diseases. The impact of an abnormal diet on the development of eccentric LVH and on ventricular function in chronic VO is unknown. This study therefore examined the effects of a fructose-rich diet on LV eccentric hypertrophy, ventricular function, and myocardial metabolic enzymes in rats with chronic VO caused by severe aortic valve regurgitation (AR). Wistar rats were divided in four groups: sham-operated on control diet (SC; n = 13) or fructose-rich diet (SF; n = 13) and severe aortic regurgitation fed with the same diets [aortic regurgitation on control diet (ARC), n = 16, and aortic regurgitation on fructose-rich diet (ARF), n = 13]. Fructose-rich diet was started 1 wk before surgery, and the animals were euthanized 9 wk later. SF and ARF had high circulating triglycerides. ARC and ARF developed significant LV eccentric hypertrophy after 8 wk as expected. However, ARF developed more LVH than ARC. LV ejection fraction was slightly lower in the ARF compared with ARC. The increased LVH and decreased ejection fraction could not be explained by differences in hemodynamic load. SF, ARC, and ARF had lower phosphorylation levels of the AMP kinase compared with SC. A fructose-rich diet worsened LV eccentric hypertrophy and decreased LV function in a model of chronic VO caused by AR in rats. Normal animals fed the same diet did not develop these abnormalities. Hypertriglyceridemia may play a central role in this phenomenon as well as AMP kinase activity.
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Carbohidratos de la Dieta/efectos adversos , Fructosa/administración & dosificación , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/efectos de los fármacos , Análisis de Varianza , Animales , Insuficiencia de la Válvula Aórtica/metabolismo , Insuficiencia de la Válvula Aórtica/fisiopatología , Western Blotting , Carbohidratos de la Dieta/metabolismo , Fructosa/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Masculino , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Volumen Sistólico , Triglicéridos/sangreRESUMEN
Aims Abnormal exercise test defined as the occurrence of exercise limiting symptoms, fall in blood pressure below baseline, or complex ventricular arrhythmias is useful to predict clinical events in asymptomatic patients with aortic stenosis (AS). The purpose of this study was to determine whether exercise-stress echocardiography (ESE) adds any incremental prognostic value to resting echocardiography in patients with AS having a normal exercise response. Methods and results One hundred and eighty-six asymptomatic patients with at least moderate AS and preserved LV ejection fraction (>/=50%) were assessed by Doppler-echocardiography at rest and during a maximum ramp semi-supine bicycle exercise test. Fifty-one (27%) patients had an abnormal exercise test and were excluded from the present analysis. Among the 135 patients with normal exercise test, 67 had an event (aortic valve replacement motivated by symptoms or cardiovascular death) at a mean follow-up of 20 +/- 14 months. The variables independently associated with events were: age >/=65 years [hazard ratio (HR) = 1.96; 95% confidence interval (CI): 1.15-3.47; P = 0.01], diabetes, (HR = 3.20; 95% CI: 1.33-6.87; P = 0.01), LV hypertrophy (HR = 1.96; 95% CI: 1.17-3.27; P = 0.01), resting mean gradient >35 mmHg (HR = 3.60; 95% CI: 2.11-6.37; P < 0.0001), and exercise-induced increase in mean gradient >20 mmHg (HR = 3.83; 95% CI: 2.16-6.67; P < 0.0001). Conclusion The exercise-induced increase in transvalvular gradient may be helpful to improve risk stratification in asymptomatic AS patients with normal exercise response. These results thus suggest that ESE may provide additional prognostic information over that obtained from standard exercise testing and resting echocardiography.
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Estenosis de la Válvula Aórtica/diagnóstico por imagen , Ecocardiografía de Estrés/métodos , Anciano , Estenosis de la Válvula Aórtica/mortalidad , Estenosis de la Válvula Aórtica/fisiopatología , Supervivencia sin Enfermedad , Ecocardiografía Doppler , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo , Factores de Riesgo , Volumen SistólicoRESUMEN
We studied by conventional and speckle-tracking echocardiography, the response of the left ventricle (LV) to a three-week continuous infusion of isoproterenol (Iso), a non-specific beta-adrenergic receptor agonist in male and female C57Bl6/J mice. Before and after Iso (30 mg/kg/day), we characterized LV morphology and function as well as global and segmental strain. We observed that Iso reduced LV ejection in both male (-8.7%) and female (-14.7%) mice. Several diastolic function parameters were negatively regulated in males and females such as E/A, E/E', isovolumetric relaxation time. Global longitudinal (GLS) and circumferential (GCS) strains were reduced by Iso in both sexes, GLS by 31% and GCS by about 20%. For the segmental LV analysis, we measured strain, strain rate, reverse strain rate, peak speckle displacement and peak speckle velocity in the parasternal long axis. We observed that radial strain of the LV posterior segments were more severely modulated by Iso than those of the anterior wall in males. In females, on the other hand, both posterior and anterior wall segments were negatively impacted by Iso. Longitudinal strain showed similar results to the radial strain for both sexes. Strain rate, on the other hand, was only moderately changed by Iso. Reverse strain rate measurements (an index of diastolic function) showed that posterior LV segments were negatively regulated by Iso. We then studied the animals 5 and 17 weeks after Iso treatment. Compared to control mice, LV dilation was still present in males. Ejection fraction was decreased in mice of both sex compared to control animals. Diastolic function parameters, on the other hand, were back to normal. Taken together, our study indicates that segmental strain analysis can identify LV regions that are more negatively affected by a cardiotoxic agent such as Iso. In addition, cessation of Iso was not accompanied with a complete restoration of cardiac function after four months.
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BACKGROUND: LV asymmetric remodeling (LVAR) is a feature commonly found in AS patients and it is presumed to be mainly related to the severity of valve stenosis. The aim of this study was to determine the associated factors and impact on left ventricular (LV) systolic function of LVAR in patients with mild and moderate aortic valve stenosis (AS). METHODS: Clinical, Doppler-echocardiographic and computed-tomographic data of 155 AS patients with preserved LV ejection fraction (≥50%) prospectively recruited in the PROGRESSA study (NCT01679431) were analyzed. LVAR was defined as a septal wall thickness ≥ 13 mm and a ratio of septal/posterior wall thickness > 1.5. LV global longitudinal strain (LV-GLS) was available in 129 patients. Plasma levels of N-terminal natriuretic B-type peptides (Nt-proBNP) were also measured. RESULTS: Mean age was 63 ± 15 years (70% men). LVAR was present in 21% (n = 33) of patients. A series of nested multivariate analysis revealed that age was the only factor associated with LVAR (all p ≤ 0.03). Additionally, these patients had higher baseline Nt-proBNP ratio (median [25-75 percentiles]: 1.04 [0.66-2.41] vs. 0.65 [0.33-1.19], p = 0.02), and significantly reduced LV-GLS (17.9[16.6-19.5] vs. 19.3[17.4-20.7] |%|, p = 0.04). A 1:1 matched analysis showed a significant association of LVAR with reduced LV-GLS (17.9[16.6-19.5] vs. 19.8[18.1-20.7] |%|, p = 0.02) and elevated Nt-proBNP (134[86-348] vs. 83[50-179]pg/ml, p = 0.03). Multivariable analysis also revealed that LVAR remains significantly associated with reduced LV-GLS (p = 0.03) and elevated Nt-proBNP (p = 0.001). LVAR was significantly associated with increased risk of major adverse cardiac events and death (Hazard ratio [95% confidence interval]: 2.32[1.28-4.22], p = 0.006). CONCLUSIONS: LVAR was found in ~20% of patients with mild or moderate AS and was not related to the degree of AS severity or concomitant comorbidities, but rather to older age. LVAR was significantly associated with reduced LV longitudinal systolic function, increased Nt-proBNP levels, and higher risk of major adverse events and death. These findings provide support for closer clinical and echocardiographic surveillance of patients harboring this adverse LV remodeling feature.
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Estenosis de la Válvula Aórtica , Disfunción Ventricular Izquierda , Anciano , Válvula Aórtica , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Volumen Sistólico , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/epidemiología , Función Ventricular Izquierda , Remodelación VentricularRESUMEN
BACKGROUND: Transthoracic echocardiography (TTE) is the reference method for evaluation of aortic stenosis (AS), and it is extensively used to quantitate left ventricular (LV) mass and volumes. Regional upper septal hypertrophy (USH) or septal bulge is a frequent finding in patients with AS and may lead to overestimation of LV mass when using linear measurements. The objective of this study was to compare estimates of LV mass obtained by two-dimensional transthoracic echocardiographic LV dimensions measured at different levels of the LV cavity with those obtained by cardiovascular magnetic resonance (CMR). METHODS: One hundred six patients (mean age, 63 ± 15 years; 68% men) with AS were included in this subanalysis of the PROGRESSA study. Two-dimensional transthoracic echocardiographic measurements of LV dimensions were obtained at the basal level (BL; as recommended in guidelines), immediately below the septal bulge (BSB), and at a midventricular level (ML). Regional USH was defined as a basal interventricular septal thickness ≥ 13 mm and >1.3 times the thickness of the septal wall at the ML. Agreement between transthoracic echocardiographic and CMR measures was evaluated using Bland-Altman analysis. RESULTS: The distribution of AS severity was mild in 23%, moderate in 57%, and severe in 20% of patients. Regional USH was present in 28 patients (26%). In the whole cohort, two-dimensional TTE overestimated LV mass (bias: BL, +60 ± 31 g; BSB, +59 ± 32 g; ML, +54 ± 32 g; P = .02). The biplane Simpson method slightly but significantly underestimated LV end-diastolic volume (bias -10 ± 20 mL, P < .001) compared with CMR. Overestimation of LV mass was more marked in patients with USH when measuring at the BL and was significantly lower when measuring LV dimensions at the ML (P < .025 vs BL and BSB). CONCLUSIONS: Two-dimensional TTE systematically overestimated LV mass and underestimated LV volumes compared with CMR. However, the bias between TTE and CMR was less important when measuring at the ML. Measurements at the BL as suggested in guidelines should be avoided, and measurements at the ML should be preferred in patients with AS, especially in those with USH.
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Estenosis de la Válvula Aórtica , Ecocardiografía , Estenosis de la Válvula Aórtica/diagnóstico , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Femenino , Ventrículos Cardíacos/diagnóstico por imagen , Humanos , Hipertrofia , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Gastrointestinal bleeding frequently complicates anticoagulant therapy causing treatment discontinuation. Data to guide the decision regarding whether and when to resume anticoagulation based on the risks of thromboembolism and recurrent bleeding are scarce. OBJECTIVES: We aimed to retrospectively evaluate the incidence of these events after anticoagulant-related gastrointestinal bleeding and assess their relationship with timing of anticoagulation resumption. METHODS: Patients hospitalized because of gastrointestinal bleeding during oral anticoagulation for any indication were eligible. All patients were followed up to 2 years after the index bleeding for recurrent major or clinically relevant non-major bleeding, venous or arterial thromboembolism, and mortality. RESULTS: We included 948 patients hospitalized for gastrointestinal bleeding occurring during treatment with vitamin K antagonists (n = 531) or direct oral anticoagulants (n = 417). In time-dependent analysis, anticoagulant treatment was associated with a higher risk of recurrent clinically relevant bleeding (hazard ratio [HR] 1.55; 95% confidence interval [CI] 1.08-2.22), but lower risk of thromboembolism (HR 0.34; 95% CI 0.21-0.55), and death (HR 0.50; 95% CI 0.36-0.68). Previous bleeding, index major bleeding, and lower glomerular filtration rate were associated with a higher risk of recurrent bleeding. The incidence of recurrent bleeding increased after anticoagulation restart independently of timing of resumption. CONCLUSIONS: Anticoagulant treatment after gastrointestinal bleeding is associated with a lower risk of thromboembolism and death, but higher risk of recurrent bleeding. The latter seemed to be influenced by patient characteristics and less impacted by time of anticoagulation resumption.