Low-Gradient Aortic Valve Stenosis – Myocardial Fibrosis and its Influence on Function and Outcome

OBJECTIVES: This prospective cohort study in patients with aortic stenosis (AS) aimed to identify surrogates of myocardial fibrosis that are easy to derive in clinical practice, allow the differentiation of low-gradient severe AS from moderate AS, and have an impact on clinical outcome. In patients with symptomatic aortic AS, a characteristic subgroup (i.e., up to one-third) exhibits severe AS with a concomitant low mean valve gradient either with preserved or reduced ejection fraction (EF). It is hypothesized that these patients tend to have an advanced stage of myocardial fibrosis and poor clinical outcome.

METHODS: Eighty-six patients with moderate or severe AS were examined by echocardiography including conventional aortic valve assessment, mitral ring displacement, and strain-rate imaging. Replacement fibrosis was quantified by late-enhancement magnetic resonance imaging. Biopsy samples were taken from patients with severe AS (n = 69) at aortic valve replacement. All patients were followed for 9 months.

RESULTS: Patients were divided into 4 groups according to aortic valve area (<1.0 cm(2)), mean valve gradient ≥40 mm Hg, and EF (<50%): group 1, moderate AS (n = 17); group 2, severe AS/high gradient (n = 49); group 3, severe AS/low gradient/preserved EF (n = 11); and group 4, severe AS/low gradient/decreased EF (n = 9). At baseline, a significant decrease in mitral ring displacement and systolic strain rate was detected in patients with low-gradient AS. In low-gradient groups, a higher degree of interstitial fibrosis in biopsy samples and more late-enhancement magnetic resonance imaging segments were observed. A close inverse correlation was found between interstitial fibrosis and mitral ring displacement (r = -0.79, p < 0.0001). Clinical outcome was best for patients in group 1, whereas mortality risk increased substantially in groups 2 through 4.

CONCLUSIONS: In severe AS, a low gradient is associated with a higher degree of fibrosis, decreased longitudinal function, and poorer clinical outcome despite preserved EF. Mitral ring displacement differentiates between moderate AS and low-gradient/severe AS with preserved EF. Ricky Jean Francois Womens Jersey

PMID: 21757118

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  1. See

    Valve replacement for severe aortic stenosis with low transvalvular gradient and left ventricular ejection fraction exceeding 0.50.
    Tarantini G, Covolo E, Razzolini R, Bilato C, Frigo AC, Napodano M, Favaretto E, Fraccaro C, Isabella G, Gerosa G, Iliceto S, Cribier A.
    Ann Thorac Surg. 2011 Jun;91(6):1808-15.

  2. Study Objectives: A prospective cohort of patients with aortic stenosis (AS) were assessed to identify surrogates of fibrosis that are readily obtainable in clinical practice, and allow the differentiation of low-gradient severe AS from moderate AS, and to impact clinical outcome

    Why was this study performed: In patients with symptomatic AS, it is believed that up to 1/3 of patients will have severe AS, but a mean gradient across the valve that is low, and have either preserved or reduced ejection fraction. It is theorized that these patients have diffuse myocardial fibrosis, and their clinical outcome is poor, and complicated by delayed intervention caused by underestimation of disease severity. This study also sought additional parameters of LV function to help differentiate moderate AS and severe AS with low-gradient, as ejection fraction is believed to be an unsatisfactory gauge of LV performance in setting of severe concentric hypertrophy.

    Study methods: 86 patients with moderate (1-1.5 cm2) or isolated symptomatic severe ( 1 cm2, < 1.5 cm2 (17 pts); 2 – severe AS, high gradient (49 pts); 3 – severe AS, low gradient, preserved EF (11 pts); 4 – severe AS, low gradient, decreased EF (9 pts). A significant decrease in mitral ring displacement and systolic strain rate was detected in patients with low gradient AS. In low gradient groups, a higher degree of interstitial fibrosis was noted in biopsy samples and increased enhancement was noted on delayed post contrast imaging. Also, a close correlation was noted between interstitial fibrosis and mitral ring displacement (r = -0.79, p < 0.0001). Mitral ring displacement and NT-proBNP were the only markers associated with fibrosis, with only mitral ring displacement retained in multivariable models for fibrosis. In patients with isolated low gradient AS, use of mitral annular displacement < 9 mm resulted in a 100% sensitivity and specificity in discriminating between moderate and severe AS. Clinical outcomes were best for patients in group 1, and mortality risk was substantially higher in groups 2-4.

    Limitations: Fairly small number of patients were in groups 3, 4. Follow up time was limited, 9 mths. 18 patients could not complete CMR due to claustrophobia. Aortic valve areas were obtained by conventional echocardiographic means, which is associated with many geometric assumptions.

    Take away points and future investigations: In this group of patients with severe AS (as measured by valve area), low valve gradients are associated with increased myocardial fibrosis, decreased longitudinal function, and worse clinical outcomes in spite of preserved EF. These findings are likely attributable to decreased longitudinal function secondary to myocardial fibrosis and small LV cavity induced by hypertrophy, with subsequent low stroke volume and dimished valve gradient. Mitral annular displacement was found to differentiate between moderate AS and low-gradient/severe AS with preserved EF, possibly because it is a closer representation of stroke volume than EF in these patients.

    Future work may include assessment of myocardial scar in patients with AS by use of T1 mapping to allow better quantification of global scar as well as characterization of distribution. Larger prospective cohorts of patients and increased follow up time with endpoints of heart failure and cardiovascular morbidity/mortality would also be of interest.

  3. In patients with severe aortic stenosis (AS) a newly recognized subgroup with low gradients represent a diagnostic and therapeutic challenge, especially because of the difficulty in discriminating patients that may not have severe AS from those that really have it, and to determine what would be their prognosis after valve replacement.

    In this paper the authors aimed (as well as accomplished) to reach several objectives:

    – To describe the global and longitudinal LV function by echo strain patterns in comparison with other subgroups with different transvalvular gradients.
    – To compare LV structure, hemodynamics, and function by cMRI, histological samples, conventional echo, and angiography.
    – To evaluate outcomes according to the valvular gradients and distinguishable features on the multimodality test mentioned.
    – To define an easily assessable LV function parameter to differentiate severe AS from non-severe AS in patients with low-gradient and preserved LV function.

    The study included 86 patients divided in four categories: Moderate AS (n=17), Severe AS with high gradients (n=49), Severe AS with low gradient and EF ≧50% (n=11), and Severe AS with low gradient and EF < 50% (n=9).

    This was a well designed descriptive study, in which all patients with severe AS underwent cardiac catheterization with invasive hemodynamics, cMRI, and valve replacement with endomyocardial biopsies. In addition, conventional echocardiography and strain pattern assessment of the radial and longitudinal function of the LV were done in all patients participating in the study.

    The results demonstrated a correlation of the amount of fibrosis on late enhancement (LE) by cMRI and biopsies with worse clinical outcomes in terms of NYHA functional class during a 9 months follow up after valve replacement.

    The most interesting finding however it was the ability of the researchers to determine a single measurable parameter as a discriminator in patients with low gradient AS and preserved EF to differentiate those patients with severe AS vs those that do not have severe AS.

    The limitations of the study rest in the small amount of patients enrolled, decreasing the statistical power of the results. Nevertheless, if the results can be validated in a larger scale, it will provide simple and easily reproducible tools that can help the clinicians to resolve important questions regarding the management of this complicated subgroup of patients.

  4. See also:

    Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis.
    Dweck MR, Joshi S, Murigu T, Alpendurada F, Jabbour A, Melina G, Banya W, Gulati A, Roussin I, Raza S, Prasad NA, Wage R, Quarto C, Angeloni E, Refice S, Sheppard M, Cook SA, Kilner PJ, Pennell DJ, Newby DE, Mohiaddin RH, Pepper J, Prasad SK.
    J Am Coll Cardiol. 2011 Sep 13;58(12):1271-9.

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