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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
  1. Ana V Villar1,2,
  2. David Merino1,2,
  3. Mareike Wenner1,
  4. Miguel Llano2,3,
  5. Manuel Cobo2,3,
  6. Cecilia Montalvo1,2,
  7. Raquel García2,4,
  8. Rafael Martín-Durán2,3,
  9. Juan M Hurlé2,5,
  10. María A Hurlé1,2,
  11. J Francisco Nistal2,4,6
  1. 1Department of Physiology and Pharmacology, University of Cantabria School of Medicine, Spain
  2. 2Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Spain
  3. 3Department of Cardiology, Hospital Universitario Marqués de Valdecilla, Spain
  4. 4Department of Cardiovascular Surgery, Hospital Universitario Marqués de Valdecilla, Spain
  5. 5Department of Anatomy and Cellular Biology, University of Cantabria School of Medicine, Spain
  6. 6Department of Surgery, University of Cantabria School of Medicine, Santander, Spain
  1. Correspondence to J Francisco Nistal, Cardiovascular Surgery, University Hospital Valdecilla, IFIMAV, Avda. de Valdecilla s/n, E 39008 Santander, Spain;jfnistal{at}gmail.com María A Hurlé, Dpt. of Physiology and Pharmacology, School of Medicine, University of Cantabria, IFIMAV, E-39011 Santander, Spain;hurlem{at}unican.es

Abstract

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 patient's 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.

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Footnotes

  • MAH and JFN contributed equally to the design and direction of the work

  • Funding This work was supported by Instituto de Salud Carlos III (PI 06-0240 and PS09/01097), Fundación Marqués de Valdecilla-Universidad de Cantabria (FMV-UC 09/01) and Instituto de Formación e Investigación Marqués de Valdecilla (FMV-API 10/20).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Comité Etico de Investigación Clínica de Cantabria, Santander, Spain.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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