Impact of cardiovascular comorbidities on echocardiographic parameters in aortic stenosis

Study population

We retrospectively analyzed data from 234 hospitalized patients obtained from electronic clinical records between 2019 and 2024 in two adjacent cardiology units. Exclusion criteria included acute myocardial infarction (MI) on admission, prior valvular surgery, and congenital aortic valve defects (with the exception of the bicuspid aortic valve).

Comorbidity assessment

Each patient was screened for the presence of AF, past MI, type 2 diabetes mellitus (T2DM), arterial hypertension, and chronic kidney disease (CKD). Pre-admission medications were documented.

Significant coronary artery stenosis was defined as a reduction of > 75% in luminal diameter in any main coronary artery or its major branches (with a 50% threshold for the left main coronary artery). Serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels were measured in 179 patients.

Echocardiographic evaluation

All patients underwent echocardiographic assessment by experienced cardiologists within 1 month of admission. Measured parameters included aortic valve area (AVA), maximal aortic valve velocity (Vmax), mean and maximal aortic valve pressure gradients (AVGmean and AVGmax), left ventricular ejection fraction (LVEF), SV, left ventricular internal dimension at end-diastole (LVIDd), left ventricular posterior wall diameter at end-diastole (LVPWd), left atrium (LA) area, interventricular septum thickness at end-diastole (IVSd), and heart rate (HR). Active AF was defined as the absence of discernible atrial A waves during echocardiographic assessment. The ratio of peak diastolic velocity of early transmitral flow to peak velocity of early diastolic mitral annular motion (E/E′ ratio) was measured in 177 patients. Echocardiographic probability of pulmonary hypertension was estimated in 225 patients.

High probability of pulmonary hypertension was defined by either mean pulmonary artery systolic pressure (mPAP) > 20 mm Hg, tricuspid regurgitation velocity (TRV) ≥ 2.9 m/s, or right ventricular systolic pressure (RVSP) > 36 mm Hg.

Left ventricular mass (LVM) was calculated using the Devereux formula and indexed to body surface area: LVM[g] = 0.8 × (1.04 × ((LVIDd + IVSd + LVPWd)³ – LVIDd³)) + 0.6.

Severe AS was defined as AVA < 1 cm², Vmax > 4 m/s, or AVGmean > 40 mm Hg. Low- and high-gradient subcategories of severe AS were defined as AVGmean < 40 mm Hg and AVGmean ≥ 40 mm Hg, respectively. Heart failure with reduced ejection fraction (HFrEF) was defined as LVEF < 40%.

Statistical analysis

The Shapiro-Wilk test was used to assess data normality. Categorical variables were compared using Pearson’s χ² test with Yates’s correction for continuity applied when appropriate. For two-group comparisons, either the Wilcoxon rank sum test or Student’s t-test was used, depending on normality. Equality of variances was assessed using Levene’s test. To exclude the confounding effect of selected echocardiographic parameters in two-group comparisons, analysis of covariance (ANCOVA) was employed with log-transformed dependent variables. Regression sub-analysis coefficients were provided for the covariate and group variable.

Statistical significance was set at p < 0.05. All statistical analyses were performed using RStudio: Integrated Development Environment for R (Posit Software, PBC, Boston, MA, USA).

Atrial fibrillation

The presence of AF in patients with AS is associated with reduced transaortic gradients, peak velocity, and SV, increasing the likelihood of low-flow-low-gradient (LF-LG) states. These LF-LG states have been associated with worse outcomes following transcatheter aortic valve implantation compared to high-gradient AS [8]. Standard practice for assessing transvalvular gradients during AF requires averaging measurements over at least 5–10 consecutive cardiac cycles [9]. Due to heart rate variability, this approach may mask high-signal gradients that would otherwise classify the defect as severe. LA dilation, reflected by increased LA area and E/E′ ratio in AF patients observed in our study, has been established as a predictor of increased postoperative risk in patients with severe AS after aortic valve replacement [10, 11]. These findings are consistent with diastolic dysfunction, which likely further exacerbates the low-flow state. The lower AVA in patients with AF seemingly suggests a more advanced valvular defect. However, this finding can be explained by reduced forward flow parameters caused by the arrhythmia. As our study population included both severely and moderately stenotic patients, those with preserved valve elasticity may exhibit markedly varying AVA measurements depending on the current flow state [9]. This hypothesis is further supported by the absence of a significant difference in AVA when comparing these same groups after adjusting for the confounding effect of SV. These findings indicate the need for a multimodal approach to AS assessment in AF patients. To prevent underestimation of AS severity and avoid inappropriate delays in intervention, additional modalities should be considered, such as aortic valve calcium measurements [4] or using single-highest Doppler signals [9, 12] instead of averaging several cardiac cycles. Our findings also underscore the importance of optimal management of concomitant diseases, particularly AF, as its presence further compromises hemodynamic function already impaired by AS. This suggests that restoration of sinus rhythm could potentially improve AS classification and delay the necessity for intervention.

Arterial hypertension

In our study, patients with arterial hypertension demonstrated smaller transaortic mean gradients. This observation aligns with the established effects of systemic hypertension on AS hemodynamics [13]. As noted in current American Heart Association guidelines [5], assessment of AS in hypertensive patients may underestimate stenosis severity due to the additional pressure load imposed on the LV beyond that caused by the narrowed valve. This extra load can result in lower Doppler velocity and a less pronounced gradient compared to normotensive individuals. This potential severity underestimation may explain the significantly higher prevalence of arterial hypertension in the moderate stenosis group observed in our study. When only moderate stenosis is identified during hypertensive states, guidelines recommend repeating measurements after achieving better blood pressure control [5].

Diabetes mellitus

Diabetes mellitus represents a significant predisposing factor in the pathogenesis of aortic valve degeneration and its progression to severe AS. This metabolic disorder exerts adverse effects on both cardiac function and structure, leading to LV remodeling and eventual cardiac failure [14]. In our study, patients with concomitant T2DM demonstrated lower LVEF values, while LA area and LVM were significantly increased. These findings align with previous research [15], highlighting the role of T2DM in the LV remodeling process, as evidenced by ventricular hypertrophy and systolic dysfunction LA morphological changes occur secondary to LV impairment resulting from AS [16], a process that may be further exacerbated by the more pronounced ventricular fibrosis and coronary microvascular dysfunction commonly observed in patients with concomitant T2DM [17].

Previous myocardial infarction

The observed reduction in LVEF, SV, and CO values in patients with previous MI aligns with impaired myocardial contractility and adverse remodeling following ischemic injury. The lower forward flow may contribute to the smaller AVA values observed through the continuity equation, potentially indicating a higher frequency of pseudo-severe AS in this population. However, previous research [18] has demonstrated that MI may induce transient acceleration of AVA decline progression independent of flow parameters. This phenomenon may be explained by the activation of systemic and local inflammatory pathways, promoting recruitment of osteogenic cells to the aortic valve through upregulation of pro-inflammatory cytokines – a mechanism currently under rigorous investigation [19, 20]. Pathophysiological changes, including increased myocardial stiffness and impaired relaxation, further exacerbate hemodynamic burden and elevate ventricular filling pressures, as evidenced by the increased E/E′ ratio in patients with previous MI. Both mechanisms likely contribute to more rapid anatomical and functional deterioration of the valve.

Chronic kidney disease

CKD is associated with accelerated progression of AS and higher mortality rates, as well as worse short- and long-term clinical outcomes following aortic valve treatment compared to AS patients with normal kidney function [21]. Assessment of severe AS with concomitant CKD presents both therapeutic and diagnostic challenges due to its unpredictable clinical course and echocardiographic limitations. For instance, measuring AVA using planimetry may be challenging due to multiple cusp calcifications frequently present in CKD patients, which can impede accurate anatomical delineation. Importantly, patients with preserved LVEF or discordant grading should undergo additional evaluation with non-contrast cardiac computed tomography due to potentially inconclusive echocardiographic findings [21].

In our study, patients with coexistent CKD demonstrated significantly lower LVEF and AVGmean. These relationships are typically observed among patients with severe AS and coexistent CKD, as both conditions contribute to volume overload and myocardial fibrosis, consequently leading to LV hypertrophy and systolic dysfunction [21].

Limitations

This study has several important limitations. Its retrospective design relies on medical record data, which may contain documentation inconsistencies or coding errors. Comorbidity assessment based on documented diagnoses might underestimate true prevalence, particularly for milder or subclinical conditions. Also, the single-center nature potentially limits generalizability to other populations and healthcare settings. Although experienced cardiologists performed echocardiographic assessments, inter-observer variability remains possible. The 1-month timeframe between admission and echocardiographic evaluation introduces temporal variability that could affect measured parameters, especially in dynamic conditions. Despite employing ANCOVA to adjust for potential confounders such as SV, residual confounding from unmeasured factors cannot be ruled out. Our focus on echocardiographic parameters does not directly assess clinical consequences of potential misclassification or the impact on treatment decisions and outcomes. Finally, we examined only a specific set of common comorbidities without deeply exploring their severity gradations. Other conditions not investigated may also influence echocardiographic parameters in AS patients. Despite these limitations, our findings provide valuable insights into the relationship between common comorbidities and echocardiographic parameters in AS.