European Heart Journal (2020) 00, 1–3
doi:10.1093/eurheartj/ehaa828
Degenerative mitral stenosis: interpreting the
meaning of mean gradient
Rebecca T. Hahn *
Columbia University Medical Center, NY Presbyterian Hospital, New York, NY, USA
..
This editorial refers to ‘Prognostic importance of the trans- ..
mitral pressure gradient in mitral annular calcification with ..
..
associated mitral valve dysfunction’, by P. B. Bertrand et al., ..
doi: 10.1093/eurheartj/ehaa819.
..
..
..
Although mitral stenosis (MS) is most commonly caused by rheumat-
..
..
ic heart disease, there is an increasing prevalence of non-rheumatic, ..
senile calcific disease or degenerative MS.1,2 Mitral annular calcifica-
..
..
tion (MAC) originates in the annulus and extends to a variable extent ..
..
onto the leaflets or myocardium, resulting in a reduced annular area ..
and leaflet restriction.3 Degenerative MS has received renewed at- ..
..
tention on the coattails of structural heart interventions in the form ..
of valve-in-MAC procedures.4 Whereas the severity of rheumatic MS
can be accurately assessed by echocardiographic mean transmitral
gradient, planimetry (by 2D or 3D methods), continuity equation,
proximal isovelocity surface area, and pressure half-time,5 these
methods have been questioned for quantifying degenerative MS.5–7
Echocardiographic Doppler-derived mean gradient in rheumatic MS
has a direct relationship to mitral valve area and is more reproducible
and accurate than direct invasive measurements, with cut-offs of <5
mmHg for mild, 5–10 mmHg for moderate, and >10 mmHg for se-
vere disease.5 The haemodynamic severity of degenerative MS has
also relied upon measurements of transvalvular gradients;5 however,
the association with gradients and outcomes in this disease has been
poorly studied.
In this setting, Bertrand et al. performed a retrospective study, pub-
lished in this issue of the European Heart Journal, using a vast single-
institution echocardiographic database to determine the natural his-
tory of significant MAC and prognosis of mean gradient in this popu-
lation.8 A total of 5754 patients were stratified by mean gradient: low
(3–5 mmHg, n = 3927), mid (5–10 mmHg, n = 1476), and high (>_10
mmHg, n = 351). After adjusting for age-, sex-, and MAC-related risk
factors (hypertension, diabetes, coronary artery disease, and chronic
kidney disease), mean gradient was independently associated with
mortality with an adjusted hazard ratio of 1.064 per 1 mmHg increase
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author: Columbia University Medical Center, New York-Presbyterian Hospital, 177 Fort Washington Avenue, New York, NY 10032, USA. Tel: þ1 212 305
7060, Fax: þ1 212 342 3660, Email: rth2@columbia.edu
Published on behalf of the European Society of Cardiology. All rights reserved. VC The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
EDITORIAL
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(confidence interval 1.049–1.080). Increasing severity of concomitant
mitral regurgitation was associated with incremental increases in
mortality only in the low gradient group. Mean transmitral gradient is
thus a continuous rather than a categorical variable with respect to
outcomes. More alarming is the increase in mortality compared with
a control group, for even the low gradient cohort, with their spline
analysis suggesting an increased hazard for death starting at a mean
gradient of 2.5 mmHg. Thus although the study adds significantly to
the literature about outcomes associated with degenerative MS, it
raises more questions about the relationship of mean gradient to
valve area and the utility of mean gradient for patient management.
The relationship between gradient and valve area is dependent
.. upon assumptions about anatomic orifice area and the effective ori-
..
.. fice area. The difference between these two measurements is
.. affected by the coefficient of orifice contraction (Cc = effective/ana-
..
.. tomic area) which reflects the principle that flow, directed to con-
.. verge toward a narrow orifice, will continue to converge beyond the
..
.. orifice.9 For flow approaching an orifice with a flat surface, the prox-
.. imal convergence has greater distal contraction (Cc  0.6) and, for
..
.. flow approaching a prolonged tube, the collimated flow has no distal
.. contraction (Cc approaches 1.0).11 These variations could result in a
..
.. 40% higher pressure gradient in the flat surface orifice (i.e. rheumatic
.. MS) for the same anatomic area and flow rate as a more tubular or
..
.. tapered orifice (i.e. degenerative MS). In addition, mean gradients are
..
.. dependent on the pressure difference between the left atrium and
.. left ventricle, and reduced left ventricular (LV) compliance frequently
..
.. seen in the elderly could also result in lower mean gradients and
.. increased mortality. In fact, compared with high gradient degenera-
..
.. tive MS patients, the low gradient subgroup in Bertrand et al.8 were
.. older with higher prevalence of hypertension, coronary artery dis-
..
.. ease, and prior myocardial infarction, and with lower ejection frac-
.. tion. Thus it is highly likely that although prognostic, mean gradients
..
.. underestimate the haemodynamic severity of degenerative MS and
.. the same cut-offs of stenosis ‘severity’ may not be relevant in this dis-
..
. ease. By the time calcific disease has caused the mean gradient to
2 Editorial

.. MAC progression was closely associated with the presence of base-

..
.. line MAC, whereas traditional cardiovascular risk factors and calcifi-
.. cation activity in bone or remote atherosclerotic areas were not
..
.. associated with disease activity or progression. Dysregulation of min-

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..
.. eral metabolism as a mechanism for the development of MAC is also
.. suggested by the strong association of the mineral biomarker fibro-
..
.. blast growth factor-23 (FGF-23), with accelerated annual progression
.. of MAC by CT calcium score in women and patients with diabetes.13
..
... Thus a cycle of calcification and inflammation may be the stimulus
.. for ongoing valvular calcification, and advanced imaging will help us
.. define the patient populations at risk (i.e. females) and test future
..
.. therapeutic interventions that interrupt this cycle. This is the theory
..
.. behind the Study Investigating the Effect of Drugs Used to Treat
.. Osteoporosis on the Progression of Calcific Aortic Stenosis
..
.. (SALTIRE II, NCT02132026) which may secondarily provide more
.. information about treatment and MAC progression. Thus, although
..
.. elevated mean transmitral gradients clearly portend a poor prognosis
.. in degenerative MS, this echocardiographic finding occurs late in the
..
.. dysregulation process, which is an important message for clinicians
..
.. treating these patients (Figure 1). Any echocardiographic evidence for
.. annular calcification may be an indication to use advanced multimo-
..
.. dality imaging14 and novel biomarkers11 since these new tools may
.. be the key to unlocking the mystery of intracardiac calcification and
..
.. allow for early detection and disease prevention.
..
.. Conflict of interest: R.T.H. reports speaker fees from Baylis
..
Figure 1 Severe degenerative mitral stenosis is shown in (A) with .. Medical, Edwards Lifescience, and Medtronic; consulting for Abbott
a tapered obstruction at the annulus and leaflets resulting in severely .. Structural, Edwards Lifesciences, Gore&Associates, Medtronic,
..
increased transmitral gradients (B) which underestimate the critical .. Navigate, and Philips Healthcare; non-financial support from 3mensio;
nature of this stenosis. (C) An example of a [18F]sodium fluoride .. and Equity with Navigate; and is the Chief Scientific Officer for the
PET scan which can detect early or, in this case late, calcium activity
..
.. Echocardiography Core Laboratory at the Cardiovascular Research
(Acknowledgement: C is courtesy of Mark Dweck). .. Foundation for multiple industry-sponsored trials, for which she
..
.. receives no direct industry compensation.
..
..
increase to >3 mmHg, it may be too late to reverse the disease
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