Cardiac structural and functional damage induced and/or increasingly aggravated by aortic valve stenosis

In the article “Long-Term Impact of Cardiac Damage Following Transcatheter Aortic Valve Replacement” recently published in JACC: Cardiovascular Interventions, Nakase et al. (1) presented their findings regarding the prognostic implications of “extra-aortic valve cardiac damages” (E-AV-CDs), detectable by echocardiography in elderly persons with aortic stenosis (AS), on long-term post-interventional patient outcomes. Strikingly, in 48% of the 1,863 investigated patients, classified into 5 severity categories according to their “cardiac damage stage” (CDSt) before transcatheter aortic valve replacement (TAVR), their CDSt revealed early after TAVR relevant changes in both directions. Thus, whereas the CDSt has improved in 30% of those patients belonging to the groups 1 to 4, it deteriorated further in 25% of those belonging to groups 0 to 3. This study is of special importance because, as it was already previously emphasized (2), the recommendations for aortic valve replacement (AVR) based only on the evidence of severe aortic valve (AV) narrowing associated with clinical symptoms considered to be related to AS, are insufficiently reliable in many individual cases. Even the addition of details about the presence of comorbidities can be insufficient for reliable therapeutic decision-making (2).

The transvalvular flow across the open AV depends mainly on the left ventricular (LV) systolic function, valve area and leaflet motility, LV geometry and diastolic filling, heart rate, arterial pressure and aortic compliance (2,3). AS-induced outflow impairment leads to an unphysiological pressure overloading of the LV which induces progressive myocardial remodeling, different from that induced by physiological exercise. Therefore, AS will eventually turn into a disease of both the AV and the LV myocardium (2,3).

Grading of AS severity is highly challenging. Echocardiographic evidence of AV thickening, calcification and reduced mobility, plus a reduced AV opening area (AVA <1.0 cm² and/or AVA index <0.6 cm²/m²) are essential indicators of relevant AS. However, even these major features cannot always be sufficient for reliable evaluations of the pathophysiological impact, the clinical severity and the prognosis of relevant AS, only from a purely aortic valvular point of view (2,3).

The opening of the AV depends on the flow rate (Q) across the AV, defined as the ratio of stroke volume (SV) and LV ejection time, and on the AV stiffness (3,4). Due to the relatively small increase of the trans-valvular mean pressure gradient (∆Pmean), the majority of patients with low gradient severe AS (LG-sAS) exhibit a low Q (<242 mL/s) which is in many cases not sufficient for the full opening of a thickened and stiff AV. This induces underestimation of both the actual planimetric AVA and the continuity equation-derived estimation of the maximal effective orifice area (3-5). Thus, the Q can adversely affect the prognostic relevance of AVA ≤1.0 cm², which is an independent predictor of mortality only in the presence of a normal trans-AV Q, but not in patients with low Q, where the prognosis of AV stenosis depends primarily on the severity of the trans-AV Q reduction (4,6-8).

AS severity grading is mainly based on the AVA, trans-AV pressure gradients and blood flow velocity. A trans-AV ∆Pmean ≥40 mmHg and/or peak jet velocity (Vmax) ≥4 m/s are the major hemodynamic alterations which together with AVA <1.0 cm² are used to define a severe AV stenosis. However, the fact that over 40% of patients with an AVA <1.0 cm² (indicative of severe AS), can have a trans-AV ∆Pmean <40 mmHg (consistent with non-severe AS), indicates that LG-sAS can considerably complicate the assessment of AS severity (3,9). Inappropriate LV myocardial adaption to severe AV narrowing due to pre-existing intrinsic myocardial alterations and/or maladaptive myocardial responses to high afterload, are typical features of LG-sAS (3). Thus, whereas AVR is recommended for symptomatic patients with high-gradient AS (HG-AS), regardless of the LV ejection fraction (LVEF), the therapeutic decision-making in patients with LG-sAS is much more demanding given that their marked LV myocardial dysfunction is by no means only a consequence of afterload-mismatch (3,10). An additional problem is also the fact that patients with LG-sAS are not a homogenous group. Thus, whereas some develop maladaptive concentric LV remodeling associated with an ejection fraction (EF) ≥50%, but a small SV index (SVi) <35 mL/m² which characterize the “paradoxical low flow LG-sAS” (PLF-LG-sAS), others develop eccentric LV hypertrophy associated with reduced EF (<50%) and either a SVi <35 mL/m² known as “low EF and low flow LG-sAS” (LEF-LF-LG-sAS) or a SVi ≥35 mL/m² known as “low EF and normal flow LG-sAS” (LEF-NF-LG-sAS) (3).

PLF-LG-sAS arises mostly in elderly women and is characterized by a small and stiff LV with particularly pronounced myocardial fibrosis (MF) and a correspondingly low SVi, despite its normal EF value. It is correlated with much worse outcomes in comparison with HG-sAS (3,11,12). Severe AS can be masked by a concomitant arterial hypertension, particularly if PLF-LG-sAS is associated with reduced systemic arterial compliance. Timely implemented AVR in symptomatic patients can significantly ameliorate the prognosis thanks to its potential to reduce the mortality rate by about 56%, whereas TAVR could be the better alternative for these patients (3).

LEF-LF-LG-sAS, which is characterized by LV eccentric remodeling and severe MF, is linked with more life-threatening heart failure. Exhibiting the most pronounced LV dilation and myocardial dysfunction, it has the poorest prognosis among all AS subtypes (3,9). The LV systolic malfunction is related to both the AS-induced afterload mismatch and already previously existing cardiovascular diseases of other etiologies (e.g., coronary artery disease). A ΔPmean ≤20 mmHg is a crucial risk factor for cardiovascular mortality regardless whether with or without AVR. If the ∆Pmean is >20 mmHg, after exclusion of severe comorbidities or post-infarction myocardial damages, percutaneous AVR might be taken into consideration for carefully selected patients (3,9).

LEF-NF-LG-sAS, which is characterized by advanced pathological LV eccentric remodeling with remarkable cavity dilatation, has a better prognosis than LEF-LF-LG-sAS. Correct diagnosis necessitates exclusion of significant AV regurgitation (AR), plus a potential overestimation of AV orifice (AVO) stenosis. In symptomatic individuals with AVO ≤0.6 cm²/m², AVR (particularly the less risky percutaneous AVR), can provide relevant benefits (3). Even adequately selected asymptomatic patients with LEF-NF-LG-sAS accompanied by relevant AR, can gain notable benefits from a timely AVR (3).

In patients with relevant AS, the LVEF is particularly dependent on the type of high afterload-induced LV myocardial responses. Thus, individuals with LV concentric remodeling can have a normal LVEF, even in the presence of a diminished SV, whereas in those with LV eccentric remodeling, a diminished LVEF can be associated with a normal SV. The presence of mitral regurgitation (MR) impairs the validity and reliability of LVEF, because the difference between the LV end-diastolic volume (LVEDV) and end-systolic volume is, not anymore, the effective SV, named also “forward SV” (fSV) and, instead, it will now be the sum of fSV and regurgitant volume (13-15). Therefore, individuals with similar LVEDV and LVEF, but different severity of MR, will have different Doppler-derived fSV values obtained directly at the LV outflow tract. LVEF overestimation by MR is avoidable by replacing the classical volume-based EF by the “forward EF” (fEF) using the Doppler-derived fSV in the formula fEF(%) = [fSV/end-diastolic volume (EDV)]•100%, which increases the validity of LVEF at simultaneous presence of AS and relevant MR (13-15). Trans-thoracic 3-dimensional echocardiography enhances the accuracy of EDV measurements (16). MR also affects misleadingly the validity and reliability of other markers of LV systolic function, like the amplitude and velocity of the mitral annular plane excursion, because the backflow into the left atrium (LA) increases the magnitude and velocity of longitudinal myocardial shortening, which can induce overestimation of LV systolic function (14,17).

In view of the points outlined above, a reliable therapeutic decision-making for patients with AS necessitates gradings of AS severity which takes into account, in addition to the degree of AV narrowing, its impact on the trans-AV blood flow and the presence of a potentially AS-related clinical symptomatology, also the severity of cardiac structural and functional damage induced and/or aggravated by the AV stenosis. In this respect, the study performed by Nakase et al. (1), is an important step toward this goal. However, given that AS grading and staging classification relates primarily to the high gradient AS (HG-AS), this classification should be further improved in the future. Thus, although PLF-LG-sAS is linked to poorer outcomes compared with severe HG-AS, and the LEF-LF-LG-sAS has the worst prognosis of all AS subtypes (3), due to the low trans-AV peak velocity and the reduced ΔPmean, according to the currently recommended grading system, these LG-sAS subtypes would be ranked only as AS grade ≤2. This in turn could delay and thus also reduce the benefits of a basically necessary TAVR, or even exclude a possibly life-saving TAVR in a relevant number of patients with underestimated sAS.

The optimized classification system used by Nakase et al. for AS categorization into 5 stages (i.e., stages 0 to 4) according to the presence or absence of E-AV-CDs detectable by echocardiography, which has proved helpful for prediction of short- and long-term outcomes after AVR, appears to be a useful complement to the currently used basic criteria for grading the severity of AS (1,2). Nevertheless, the independent (not additive) use of the presence or absence of certain cardiac damages (CDs) could create important challenges regarding the appraisal of the collected data. Thus, the additional presence of either a pulmonary hypertension (PH) with pulmonary arterial systolic pressure (PASP) ≥60 mmHg or a relevant tricuspid regurgitation (TR), regardless of the presence or absence of LA dilation or MR, which both characterize the stage-2 of CDs, will not always reflect a stage-3 AS-related CD. In such cases first of all it is necessary to exclude a coexistent precapillary PH, which in turn requires also details about the LA and the mitral valve. Similarly, in the presence of an AVA <1.0 cm², the detection of a moderate-severe right ventricular (RV) dysfunction, without neither evidence of LA dilation or MR (which characterize the stage-2) nor a PASP ≥60 mmHg (which is a key feature for stage-3), would suggest either the coexistence of RV dysfunction not related to the AS, or the possible existence of additional pathomechanisms, different from that triggered by RV pressure overloading, which might be involved in the development of an AS-related RV dysfunction. The latter could explain at least in part the discrepancy ascertained by Nakase et al. (1) between the highly relevant post-TAVR reduction of the PASP ≥60 mmHg prevalence in patients belonging to stage-3 and the only modest reduction of RV dysfunction prevalence in patients belonging to stage-4. This discrepancy may suggest that many of the patients assigned to the stage-4 group had RV dysfunction which was not mainly induced by the AS-related increase in the pulmonary vascular resistance (PVR). In a study which included patients with AVA <1.0 cm², PH did not predict RV dysfunction and RV dysfunction was more common in patients with LG-sAS than in patients with HG-sAS (18). The only predictor of RV dysfunction was found to be the LV dysfunction, which was presumed to be mainly based on a ventriculo-ventricular interaction (VVI) between the LV and RV, an assumption which was supported by the significant correlation which was found between the LVEF and right ventricular ejection fraction (RVEF) (18). Important indicators for a relevant role of a close VVI were also provided by a study on patients with sAS accompanied by isolated post-capillary mild PH in 63% and reduced RV function in 50% of them (19). In that study, the acute improvement of RV function after TAVR (i.e., increase in tricuspid lateral annular systolic velocity and RV stroke work) was hardly explainable only by RV afterload reduction because, despite the PVR reduction, the PASP did not change significantly (19). On the other hand, post-TAVR acute improvement of LV ejection could explain the improvement of RV function through the “crosstalk” between the LV and RV, given that the magnitude of RV improvement appeared directly correlated with the post-TAVR increase in the AVA. Thus, the categorization of the different types of AS-related CDs like LV dysfunction, LA enlargement, PH and RV dysfunction into distinct stages should be further optimized because the clinically more relevant stages 2,3 and 4 are clearly interrelated.

An analysis of 689 patients undergoing TAVR revealed a significant association between the extent of E-AV-CDs and post-TAVR all-cause mortality, which indicated that the above-described AS staging could improve risk stratification, assessment of prognosis and decision-making for potential TAVR candidates (20). That study also revealed important aspects regarding the compatibility between the currently used criteria for of AS severity grading and the 5 severity stages according to the presence or absence of E-AV-CDs (20). Thus, in patients undergoing TAVR, although the baseline AVA was, as expected, decreasingly lower along the stages 1 to 4, there was a gradually reduction of the trans-AV ∆Pmax along the stages and also an increasing prevalence of ΔPmean values <40 mmHg from 22% in severity stage-1 to 36% in stage-4 (20). The discrepancy between these data and the currently used grading system, where lower trans-AV ΔPmean and Vmax values (i.e., <40 mmHg and <4 m/s, respectively) indicate a less severe AS, could be explainable by the relatively high prevalence of LG-AS among the patients who were included into the above-mentioned study. Thus, whereas the prevalence of LG-AS in the stage-1 group was 21.5%, in the stage-4 group its prevalence reached 57% (20).

Understanding and considering the morphological and functional distinctive features of the different types and subtypes of AS helps to avoid possible under- or overestimation of AS severity, because each of them can have unfavorable repercussions on patient outcome. Staging the disease rather than classifying the AS solely by valve hemodynamics appears mandatory. Despite of its limitations in accurate severity grading of LG-AS subtypes, echocardiography remains a main tool for diagnosing AV stenosis and evaluation of both AS-related cardiac alterations and E-AV-CDs. However, it is time to find a consensus concerning the most optimal integration and inter-connection of the current AS severity grading recommendation with the severity stages related to the presence or absence of E-AV-CDs.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Cardiovascular Diagnosis and Therapy. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-380/coif). The author has no conflicts of interest to declare.

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