Load independent impairment of reverse remodeling after valve replacement in hypertensive aortic stenosis patients

https://doi.org/10.1016/j.ijcard.2013.11.006Get rights and content

Abstract

Background

We evaluated the impact of hypertension on the left ventricular mass regression in aortic stenosis after aortic valve replacement.

Methods

We prospectively studied 135 patients with severe aortic stenosis at baseline and 1 year after surgery. In 32 patients we analyzed myocardial gene expression of collagen types I and III, connective tissue growth factor, transforming growth factor-β1, metalloproteinase-2 and its tissue inhibitor and compared its levels vs controls.

Results

Seventy-six patients (56.3%) had a history of hypertension. Hypertensive patients were older, had higher Euroscore-II and NYHA class, with no differences in stenosis severity. At 1 year follow-up there was a median decrease of mass index of 14.2% (P25–75: − 4.3%–30.4%; p < 0.001). Mass regression was significantly higher in patients without hypertension, with a median decrease of 25.9% (P25–75: 12.0%–38.7%) vs 5.4% (P25–75: − 12.5%–20.1%; p = 0.001), despite similar increase in effective orifice area and no differences in valvuloarterial impedance. After 1 year, higher baseline left ventricular mass index (p = 0.005) and the absence of hypertension (p = 0.002) or diabetes (p = 0.041) were the only independent predictors of mass regression higher than the median. Comparing with controls, aortic stenosis patients had an increased expression of collagen types I and III, but only hypertensive patients had higher relative expression of collagen type I vs III. In hypertensive patients TIMP2 expression was up-regulated and correlated with higher baseline left ventricular mass index (r = 0.61; p = 0.020).

Conclusions

In aortic stenosis, hypertension impairs mass regression one year after valve replacement, independently of total afterload. Differences in the expression of extracellular matrix remodeling genes might contribute to this finding.

Introduction

Hypertension (HT) is a common comorbidity in patients with aortic valve stenosis (AS), with a previously reported prevalence of 33–72% [1], [2], [3], [4].

In chronic pressure overload states, like systemic HT and AS, the left ventricle (LV) responds with hypertrophy and altered geometry as an adaptative mechanism that helps to maintain contractile performance despite abnormal loading conditions. LV hypertrophy (LVH) allows for normalization of systolic wall stress and has been considered as compensatory [5], but it is also associated with impaired coronary blood-flow reserve [6] and changes in cardiomyocytes and extracellular matrix (ECM) connective tissue, some of them irreversible [7]. Moreover, the presence of residual hypertrophy after aortic valve replacement (AVR) has been associated with incomplete recovery of left ventricular function and worse prognosis [8], [9], [10].

The coexistence of hypertension and valvular aortic stenosis (AS) is common, but few studies have assessed the impact of concomitant hypertension on LV structure and function in patients with AS. Moreover, although we have evidence of changes in the composition and structure of ECM in the progression to heart failure in AS [11] and HT [4], there is no published data comparing the expression of genes regulating ECM production in patients with both types of pressure overload.

Therefore our aim was to evaluate the importance of HT on LV remodeling and LV mass regression in AS patients one year after AVR. Additionally, we did a subgroup analysis on myocardial expression of genes involved in ECM remodeling in aortic stenosis patients with and without HT, and compared its results with those of a control group.

Section snippets

Patient selection and follow-up

Between January 2006 and December 2009 we included 141 consecutive patients over 18 years old with severe symptomatic AS (aortic valve area < 1 cm2 or mean transaortic gradient ≥ 40 mm Hg) referred for aortic valve replacement (AVR) at the Cardiothoracic Surgery Department of Hospital São João, Porto, Portugal. This investigation conforms to the Declaration of Helsinki, had institutional ethical review board approval and each study participant signed an informed consent before enrolment. We excluded

Results

Demographics and clinical parameters of the 135 patients with severe symptomatic AS are described in Table 1. Heart failure was the most prevalent presentation feature (81.5%), 72 (53.3%) patients had echocardiographic evidence of LV diastolic dysfunction and most patients had LVH (68.1%) with a mean LVM index of 129.6 ± 34.0 g/m2 (Table S1, Supplementary data). Ninety nine cases (73.3%) had a bioprosthesis implanted (size 21 mm: 46.6%; 23 mm: 27.4%; 25 mm: 14.8%; 19 mm: 10.5%; and 17 mm: 0.7%). The

Correlations between clinical data and myocardial expression of extracellular matrix remodeling components

We analyzed mRNA expression in the LV of 9 controls and 32 patients with severe AS, 19 of which also had hypertension (Fig. 2, Fig. 3). Comparing with controls, patients with AS had significantly higher levels of collagen types I (AS 2.57 ± 0.34 vs CTRL 1.00 ± 0.14; p < 0.001) and III expression (AS 1.94 ± 0.25 vs CTRL 1.00 ± 0.13; p = 0.003), with no differences in the expression of CTGF, TGFβ1, MMP2 or TIMP2. Both HT + AS and ASwHT have an increase expression in collagens type I (HT + AS: 2.88 ± 1.68 vs 1.00 ± 

Discussion

This is a prospective study of patients with isolated severe AS analyzing the impact of HT on LV mass regression and reverse remodeling. Overall, baseline LVM index and the absence of HT and DM were the only independent predictors of LVM regression at one year follow-up. In addition, we report two major findings. First, HT impairs LV mass regression and reverse remodeling after AVR, independently of total LV afterload. Secondly, the combination of HT with AS is associated with a different

Study limitations

Although our study is hypothesis generating, it has some limitations: (1) Our evaluation was done one year after AVR because in the literature significant LVM regression is maximal after the first year, and has only a non-significant slight decrease after 18 months to 10 years [25], [44], [45]. To know if HT definitely impairs LV mass regression or if it only makes it slower a longer follow-up period is needed. (2) At follow-up blood pressure values were determined only at office visit. Given

Conclusions

Our results, showing that HT in AS is associated with ECM remodeling favoring collagen deposition and higher LVM, together with the negative impact of HT on LV mass regression and reverse remodeling after AVR, gives strength to the concept of modulation of the RAAS system in AS, particularly if HT is also present. Therefore, therapeutic intervention with antagonists of the RAAS is very appealing, especially considering the pro-hypertrophic and pro-fibrotic effects of angiotensin II. New and

Acknowldgements

This work was supported by the Cardiovascular R&D Center, through grants from the Portuguese Foundation for Science and Technology (PEst-C/SAU/UI0051/2011, EXCL/BIM-MEC/0055/2012 and HMSP-ICS/0007/2012; partially funded by FEDER through COMPETE) and from the European Commission (FP7-Health-2010; MEDIA-261409).

References (45)

  • K. Linhartova et al.

    Severe aortic stenosis and its association with hypertension: analysis of clinical and echocardiographic parameters

    Blood Press

    (2007)
  • Rieck AE, Cramariuc D, Staal EM, Rossebo AB, Wachtell K, Gerdts E. Impact of hypertension on left ventricular structure...
  • R. Querejeta et al.

    Increased collagen type i synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis

    Circulation

    (2004)
  • J.F. Spann et al.

    Ventricular performance, pump function and compensatory mechanisms in patients with aortic stenosis

    Circulation

    (1980)
  • M.L. Marcus et al.

    Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries

    N Engl J Med

    (1982)
  • H.P. Krayenbuehl et al.

    Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement

    Circulation

    (1989)
  • J. Lessick et al.

    Failure of left ventricular hypertrophy to regress after surgery for aortic valve stenosis

    Echocardiography

    (2002)
  • K. Taniguchi et al.

    Left ventricular mass: impact on left ventricular contractile function and its reversibility in patients undergoing aortic valve replacement

    Eur J Cardiothorac Surg

    (2007)
  • S. Heymans et al.

    Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart

    Circulation

    (2005)
  • I. Falcao-Pires et al.

    Correlation between plasma levels of apelin and myocardial hypertrophy in rats and humans: possible target for treatment?

    Expert Opin Ther Targets

    (2010)
  • B.R. Lindman et al.

    The adverse impact of diabetes mellitus on left ventricular remodeling and function in patients with severe aortic stenosis

    Circ Heart Fail

    (2011)
  • I. Falcao-Pires et al.

    Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness

    Circulation

    (2011)

    • Cited by (0)

    1

    These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

    View full text
    Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.