Manuel Cobo

Myocardial and circulating levels of microRNA-21 reflect left ventricular fibrosis in aortic stenosis patients

BACKGROUND Various human cardiovascular pathophysiological conditions associate aberrant expression of microRNAs (miRNAs) and circulating miRNAs are emerging as promising biomarkers. In mice, myocardial miR-21 overexpression is related to cardiac fibrosis elicited by pressure overload. This study was designed to determine the role of myocardial and plasmatic miR-21 in the maladaptive remodeling of the extracellular matrix induced by pressure overload in aortic stenosis (AS) patients and the clinical value of miR-21 as a biomarker for pathological myocardial fibrosis. METHODS In left ventricular biopsies from 75 AS patients and 32 surgical controls, we quantified the myocardial transcript levels of miR-21, miR-21-targets and ECM- and TGF-β-signaling-related elements. miR-21 plasma levels were determined in 25 healthy volunteers and in AS patients. In situ hybridization of miR-21 was performed in myocardial sections. RESULTS The myocardial and plasma levels of miR-21 were significantly higher in the AS patients compared with the controls and correlated directly with the echocardiographic mean transvalvular gradients. miR-21 overexpression was confined to interstitial cells and absent in cardiomyocytes. Using bootstrap validated multiple linear regression, the variance in myocardial collagen expression was predicted by myocardial miR-21 (70% of collagen variance) or plasma miR-21 (52% of collagen variance), together with the miR-21 targets RECK and PDCD4, and effectors of TGF-ß signaling. CONCLUSIONS Our results support the role of miR-21 as a regulator of the fibrotic process that occurs in response to pressure overload in AS patients and underscore the value of circulating miR-21 as a biomarker for myocardial fibrosis.

BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-β signaling

Left ventricular (LV) pressure overload is a major cause of heart failure. Transforming growth factors-β (TGF-βs) promote LV remodeling under biomechanical stress. BAMBI (BMP and activin membrane-bound inhibitor) is a pseudoreceptor that negatively modulates TGF-β signaling. The present study tests the hypothesis that BAMBI plays a protective role during the adverse LV remodeling under pressure overload. The subjects of the study were BAMBI knockout mice (BAMBI(-/-)) undergoing transverse aortic constriction (TAC) and patients with severe aortic stenosis (AS). We examined LV gene and protein expression of remodeling-related elements, histological fibrosis, and heart morphology and function. LV expression of BAMBI was increased in AS patients and TAC-mice and correlated directly with TGF-β. BAMBI deletion led to a gain of myocardial TGF-β signaling through canonical (Smads) and non-canonical (TAK1-p38 and TAK1-JNK) pathways. As a consequence, the remodeling response to pressure overload in BAMBI(-/-) mice was exacerbated in terms of hypertrophy, chamber dilation, deterioration of long-axis LV systolic function and diastolic dysfunction. Functional remodeling associated transcriptional activation of fibrosis-related TGF-β targets, up-regulation of the profibrotic micro-RNA-21, histological fibrosis and increased metalloproteinase-2 activity. Histological remodeling in BAMBI(-/-) mice involved TGF-βs. BAMBI deletion in primary cardiac fibroblasts exacerbated TGF-β-induced profibrotic responses while BAMBI overexpression in NIH-3T3 fibroblasts attenuated them. Our findings identify BAMBI as a critical negative modulator of myocardial remodeling under pressure overload. We suggest that BAMBI is involved in negative feedback loops that restrain the TGF-β remodeling signals to protect the pressure-overloaded myocardium from uncontrolled extracellular matrix deposition in humans and mice.

Myocardial gene expression of microRNA-133a and myosin heavy and light chains, in conjunction with clinical parameters, predict regression of left ventricular hypertrophy after valve replacement in patients with aortic stenosis

Background Left ventricular (LV) reverse remodelling after valve replacement in aortic stenosis (AS) has been classically linked to the hydraulic performance of the replacement device, but myocardial status at the time of surgery has received little attention. Objective To establish predictors of LV mass (LVM) regression 1 year after valve replacement in a surgical cohort of patients with AS based on preoperative clinical and echocardiographic parameters and the myocardial gene expression profile at surgery. Methods Transcript levels of remodelling-related proteins and regulators were determined in LV intraoperative biopsies from 46 patients with AS by RT-PCR. Using multiple linear regression analysis, an equation was developed (adjusted R2=0.73; p<0.0001) that included positive [preoperative LVM, microRNA-133a, serum response factor (SRF, which is known to be a transactivator of miR-133) and age] and negative [body mass index (BMI), Wolf-Hirschhorn syndrome candidate-2 (WHSC2, which is a target for repression by miR-133a), β-myosin heavy chain, myosin light chain-2, diabetes mellitus, and male gender] independent predictors of LVM reduction. Results Aortic valve area gain or the reduction in transvalvular gradient maintained no significant relationships with the dependent variable. Logistic regression analysis identified microRNA-133a as a significant positive predictor of LVM normalisation, whereas β-myosin heavy chain and BMI constituted negative predictors. Conclusions Hypertrophy regression 1 year after pressure overload release is related to the preoperative myocardial expression of remodelling-related genes, in conjunction with the patients clinical background. In this scenario, miR-133 emerges as a key element of the reverse remodelling process. Postoperative improvement of valve haemodynamics does not predict the degree of hypertrophy regression or LVM normalisation. These results led us to reconsider the current reverse remodelling paradigm and (1) to include criteria of hypertrophy reversibility in the decision algorithm used to decide timing for the operation; and (2) to modify other prevailing factors (overweight, diabetes, etc) known to maintain LV hypertrophy.

Androgens Contribute to Sex Differences in Myocardial Remodeling under Pressure Overload by a Mechanism Involving TGF-β

Background In clinical studies, myocardial remodeling in aortic valve stenosis appears to be more favorable in women than in men, even after menopause. In the present study, we assessed whether circulating androgens contribute to a less favorable myocardial remodeling under pressure overload in males. We examined sex-related differences in one-year-old male and female mice. Whereas male mice at this age exhibited circulating androgen levels within the normal range for young adults, the circulating estrogens in females were reduced. The contribution of gonadal androgens to cardiac remodeling was analyzed in a group of same-age castrated mice. Methodology/Principal Findings Animals were subjected to transverse aortic constriction (TAC). Echocardiography was performed 2 weeks after TAC and myocardial mRNA levels of TGF-βs, Smads 2 and 3, collagens, fibronectin, β-myosin heavy chain and α-myosin heavy chain were determined by q-PCR. Protein detection of p-SMAD2/3 was performed by Western Blot. Histological staining of fibrosis was performed with picrosirius red and Massons trichrome. Compared with females, males developed more severe tissue fibrosis, LV dilation and hemodynamic dysfunction. TAC-males showed higher myocardial expression levels of TGF-βs and the treatment with a neutralizing antibody to TGF-β prevented myocardial fibrosis development. Orchiectomy diminished TAC-induced up-regulation of TGF-βs and TGF-β target genes, and it also reduced fibrosis and hemodynamic dysfunction. The capability of androgens to induce TGF-β expression was confirmed in NIH-3T3 fibroblasts and H9C2 cardiomyocytes exposed to dihydrotestosterone. Conclusions/Significance Our results indicate that circulating androgens are responsible for the detrimental effects in the myocardium of older male mice subjected to pressure overload through a mechanism involving TGF-βs.

Circulating Levels of miR‐133a Predict the Regression Potential of Left Ventricular Hypertrophy After Valve Replacement Surgery in Patients With Aortic Stenosis

Background Myocardial microRNA‐133a (miR‐133a) is directly related to reverse remodeling after pressure overload release in aortic stenosis patients. Herein, we assessed the significance of plasma miR‐133a as an accessible biomarker with prognostic value in predicting the reversibility potential of LV hypertrophy after aortic valve replacement (AVR) in these patients. Methods and Results The expressions of miR‐133a and its targets were measured in LV biopsies from 74 aortic stenosis patients. Circulating miR‐133a was measured in peripheral and coronary sinus blood. LV mass reduction was determined echocardiographically. Myocardial and plasma levels of miR‐133a correlated directly (r=0.46, P<0.001) supporting the myocardium as a relevant source of plasma miR‐133a. Accordingly, a significant gradient of miR‐133a was found between coronary and systemic venous blood. The preoperative plasma level of miR‐133a was higher in the patients who normalized LV mass 1 year after AVR than in those exhibiting residual hypertrophy. Logistic regression analysis identified plasma miR‐133a as a positive predictor of the hypertrophy reversibility after surgery. The discrimination of the model yielded an area under the receiver operator characteristic curve of 0.89 (P<0.001). Multiple linear regression analysis revealed plasma miR‐133a and its myocardial target Wolf‐Hirschhorn syndrome candidate 2/Negative elongation factor A as opposite predictors of the LV mass loss (g) after AVR. Conclusions Preoperative plasma levels of miR‐133a reflect their myocardial expression and predict the regression potential of LV hypertrophy after AVR. The value of this bedside information for the surgical timing, particularly in asymptomatic aortic stenosis patients, deserves confirmation in further clinical studies.

Utility of implantable loop recorders for diagnosing unexplained syncope in clinical practice.

Establishing a symptom–rhythm correlation in patients with unexplained syncope is complicated because of its sporadic, infrequent, and unpredictable nature. Prolonged monitoring with an implantable loop recorder (ILR) allows the recording of electrocardiogram (ECG) data from a spontaneous syncopal event.

Current Surgical Treatment of Calcified Aortic Stenosis

Currently, aortic stenosis is the main indication for cardiac surgery in western countries. With the aim of describing the clinical and surgical characteristics and the short-term outcome of current surgical treatment, we carried out a retrospective study of 238 patients (mean age 71 years, 43% female) who underwent surgery during 2002-2003. Of these, 73% had a EuroSCORE >6. Surgical procedures included isolated aortic valve replacement in 61%, ascending aorta surgery in 14%, coronary artery by-pass grafting in 21%, and mitral surgery in 4%. The in-hospital mortality rate in the 30 days after surgery was 7.1%. Multivariate analysis, adjusted for age, sex and left ventricular ejection fraction, showed that only concomitant coronary artery by-pass grafting was significantly associated with in-hospital mortality (odds ratio=4; P=.019). Factors associated with mortality at 18 months were: previous neurological disease (hazard ratio [HR]=3.25; P=.017), prosthesis diameter <21 mm (HR=2.86; P=.018), and coronary artery by-pass grafting (HR=2.35; P=.05).

Spanish Heart Transplant Registry. 29th Official Report of the Spanish Society of Cardiology Working Group on Heart Failure

INTRODUCTION AND OBJECTIVES The present report updates the characteristics and results of heart transplantation in Spain, mainly focused in the 2008-2017 period. METHODS We describe the recipient and donor characteristics, surgical procedures, and outcomes of heart transplants performed in 2017. The 2017 data were compared with those obtained from 2008 to 2016. RESULTS A total of 304 cardiac transplants were performed in 2017. Between 1984 and 2017, 8173 procedures were performed, 2689 of them after 2008. Significant temporal trends were observed in recipient characteristics (lower pulmonary vascular resistance, lower use of mechanical ventilation, and a higher percentage of diabetic patients and those with previous cardiac surgery), donor characteristics (older donor age and a higher percentage of female donors and those with a prior cardiac arrest) and procedures (lower ischemia time). In 2017, 27% of patients were transplanted after undergoing mechanical ventricular assistance (P <.001 for trend). In the last decade, there was a trend to better survival. CONCLUSIONS Around 300 transplants per year were performed in Spain in the last decade. There was a significant increase in the use of pretransplant mechanical circulatory support and a trend to improved survival.