Baseline characteristics

In total, 1320 datasets/patients were included in the study. Cardiovascular risk factors as baseline characteristics in patients with AR were analyzed depending on the severity of the vitium, and patients separated into five groups (no AR, minimal AR, mild AR, moderate AR, and severe AR) accordingly (Table 1). Overall, the most common cardiovascular risk factors in AR were arterial hypertension (73%), previous ischemic stroke (65%), and atrial fibrillation (30.5%). Increased age was significantly correlated with the severity of AR, except for severe AR, which showed a lower patient age. Correlation of cardiovascular risk factors associated with the severity of AR was observed for ischemic stroke, coronary heart disease, heart failure, diabetes mellitus, renal failure, and atrial fibrillation. Hyperlipidemia, obesity, and PAD decreased in frequency with an increasing severity of AR in this patient cohort. The risk factors coronary heart disease, arterial hypertension, diabetes mellitus and atrial fibrillation were more frequent in patients with AR compared to patients without detection of this vitium.

Table 1 Baseline characteristics of patients with aortic valve regurgitation (AR)

Patients with aortic valve stenosis showed a similar pattern of baseline characteristics compared to patients with AR (Table 2). The most common cardiovascular risk factors were arterial hypertension (85%), previous stroke (69%) and atrial fibrillation (43%). Increase in severity of AS was associated significantly with patients’ age. An increased frequency of heart failure, diabetes and obesity was also associated with severity of AS. Overall, patients with AS showed hyperlipidemia, PAD, renal failure, and arterial hypertension more often than patients without AS, whereas coronary heart disease, diabetes mellitus, smoking, and obesity were more common in patients without AS.

Table 2 Baseline characteristics of patients with aortic valve stenosis (AS)Doppler flow profile characteristics in patients with aortic valve regurgitation

In patients without AR, AR-associated flow profile changes were only detectable in nvUS in singular cases, most often in CCA, less frequent in ICA but never in both vessels (Table 3, full data included in Additional file 1). In minimal AR, only one patient showing nvUS flow profile changes was identified, displaying a ‘bisferious pulse’ in ICA. The frequency of changes in flow profiles increased coherent with the severity of AR. Overall, most changes of flow patterns were identified in CCA. The characteristics ‘bisferious pulse’ and ‘no dicrotic notch’ were found to be more common in CCA than in ICA and their frequency increased associated with the severity of AR (‘bisferious pulse’ in CCA in mild AR 14.2%, moderate AR 21.9%, severe AR 25%, ‘no dicrotic notch’ in CCA 15.6% in mild AR, 31.3% in moderate AR). In severe AR, flow characteristic ‘zero flow’ and ‘diastolic reversal’ appeared additionally in 50% of cases in the CCA, whereas these flow changes were only detected in a small percentage of patients with mild or moderate AR.

Table 3 nvUS flow characteristics in patients with AR

Regarding ICA, ‘bisferious pulse’ remained the most common flow alteration (approx. 12% of patients), followed by ‘diastolic reversal’ (ca. 11%). Although flow alterations in ICA were less frequent in comparison to CCA, an increased appearance was associated with severity of the valvular pathology as well. ‘Bisferious pulse’ and ‘diastolic reversal’ showed a highly significant association with AR in all evaluated carotid parts (singular and combined, p < 0.001). In singular and combined evaluation of CCA and ICA, association of AR and ‘no dicrotic notch’ was significant as well (p < 0.001). Interestingly, if ECA was considered, correlation significance decreased (p 0.011). The flow pattern ‘zero diastole’ was found to be significantly associated (p < 0.001) with AR only in CCA.

Overall, sensitivity was low (0.2–15.56%) due to the high number of patients without AR in this model. The positive prediction value (PPV) was found to be  > 90% for all evaluated flow characteristics in all examined vessels, despite ‘diastolic reversal’ in ICA (PPV = 50%). Moreover, specificity was detected to be  > 99% for all examined parameters, underlining a high probability of absence of cardiac valve pathology in patients without flow pattern alterations. Negative prediction value (NPV) was found to be approximately 65% (63–66%) for all flow patterns.

To improve differentiation of patients with clinically significant cardiac valve pathology, patients without AR were compared to patients with at least moderate AR (including patients with moderate and severe AR, Fig. 4, Table 4, full data included in Additional file 1). Patients with minimal and mild AR were excluded from this analysis. In the group without vitium, no flow pattern changes were detected simultaneously in CCA and ICA. In patients with at least moderate AR, ‘no dicrotic notch’ was the most common flow deviation in the CCA (31% of patients) followed by ‘bisferious pulse’ (22%), ‘diastolic reversal’ (14%), whereas in ICA ‘bisferious pulse’ presented as the most common flow alteration (19%). Overall, flow pattern changes were more common in CCA than ICA, resulting in higher sensitivity of CCA compared to ICA. Nevertheless, the lowest sensitivity was detected for flow pattern changes in both vessels. Corresponding, positive predictive values were found to be close to 100% when assessing CCA and ICA, 90–100% in ICA and 81–97% in CCA. Specificity remained high, showing results of 100% specificity for combined evaluation of CCA and ICA, the lowest specificity was detected for singular analysis of CCA (99.4–99.88%).

Fig. 4

Distribution of Doppler flow curve characteristics in AR

Table 4 nvUS flow characteristics ‘no AR’ compared to at least ‘moderate AR’Doppler flow profile characteristics in patients with aortic valve stenosis

Patients without detection of aortic valve stenosis in echocardiogram showed ‘pulsus tardus et parvus’ in CCA in three cases (0.2%) (Table 5). Overall, 85% of patients with AS showed flow pattern changes in CCA and 75% in ICA. In combined evaluation of CCA and ICA, 53% of patients showed abnormal waveforms in nvUS. Moreover, frequency of nvUS alterations increased corresponding to the severity of the AS for all evaluated vessels (CCA, ICA, CCA + ICA, CCA + ICA + ECA). Interestingly, all patients with severe AS showed ‘pulsus tardus et parvus’ in nvUS in at least one evaluated vessel, displaying a significant correlation (p < 0.001) for AS and the appearance of ‘pulsus tardus et parvus’ in all examined parts of the carotid arteries.

Table 5 nvUS flow characteristics in patients with AS

Sensitivity was found to be highest in CCA (85%) and decreased slightly in ICA (75%). The lowest sensitivity (53%) was found for a combined analysis of CCA, ICA and ECA, with a positive predictive value of 100%. Sensitivity increased when only CCA and ICA were considered (69%), underlining reduced sensitivity for flow pattern deviations in ECA. A lack of flow pattern changes was detected with a specificity of ca. 100%, negative prediction values were found to be between 97 and 99%.

When data for patients with at least moderate AS and severe AS was evaluated together in comparison to absence of AS in echocardiogram, ‘pulsus tardus et parvus’ was found to be apparent most often in CCA (92% of patients) (Table 6, Fig. 5). In ICA, 84% of patients showed a flow deviation, whereas nvUS delivered conspicuous results in both CCA and ICA in 79% of patients with AS. Statistical analysis revealed a highly significant correlation between AS and the appearance of ‘pulsus tardus et parvus’ in all evaluated parts of the carotid vessels (p < 0.001). Sensitivity increased to 92% in CCA and 84% in ICA, whereas specificity and negative predictive value remained mainly unchanged, underlining a good prediction probability.

Table 6 nvUS flow characteristics in patients with ‘no AS’ compared to at least ‘moderate AS’Fig. 5

Distribution of Doppler flow curve characteristics in AS

Statistical relationship between aortic valve regurgitation and nvUS flow profile changes

A logistic regression analysis was performed to evaluate causality between nvUS flow pattern changes and cardiac valve disease (Table 7). Patients without AR and minimal-to-mild AR were compared to a cohort of patients with moderate or severe AR.

Table 7 Results of regression analysis for aortic valve regurgitation

All evaluated flow pattern characteristics were predictive for the existence of at least moderate AR. Highest predictive value was found for ‘no dicrotic notch’, especially when detected in CCA and ICA simultaneously, therefore, ‘no dicrotic notch’ seems to possess the most causal relationship with AR. The flow characteristic ‘diastolic reversal’ was associated with AR in all parts of the carotid arteries and showed a high predictive value in the ICA and in the CCA. Interestingly when CCA and ICA are assessed combined, odds ratio for ‘diastolic reversal’ was higher than for ‘bisferious pulse’. ‘Bisferious pulse’ delivered the highest predictive value when detected either in CCA and ICA or singularly in ICA. Overall, the flow characteristic ‘zero flow’ showed the least predictive value for AR. Analysis of ICA and combination of CCA and ICA was not possible due to insufficient case numbers displaying this flow pattern alteration in ICA. To conclude, the described characteristic flow patterns appear in increased frequency associated with the severity of AR, especially in CCA and ICA. Although flow deviations are more common in CCA, assessment of ICA increases specificity, which is underlined by the increased odds ratio in ICA and in the combined evaluation of both vessel parts.

Statistical relationship between aortic valve stenosis and nvUS flow profile changes

Regression analysis for the flow pattern ‘pulsus tardus et parvus’ in nvUS and AS was performed, showing a significant relationship (p < 0.001) between the cardiac vitium and altered Doppler flow profile in carotid vessels. Patients with at least moderate AS were compared to patients without or mild AS (Table 8). Odds ratio for ‘pulsus tardus et parvus’ and AS was found to be high, especially if the flow profile was detected in CCA, ICA or both vessels, showing a high predictive value of this flow alteration for AS. Although assessment of ECA delivered a slightly lower predictive value compared to the other parts of the carotid vessels, a combined analysis of all vessel parts (CCA + ICA + ECA) yielded the highest predictive value.

Table 8 Results of regression analysis for aortic valve stenosisInter-rater reliability

Twenty patients enrolled in the study were randomly chosen and the Doppler flow curve images were judged by a second rater with substantial (> 10 years) experience in neurovascular ultrasound. The second rater was blinded for the TEE and clinical data as well. Inter-rater reliability for the right and left common carotid artery was substantial (κ 0.671, p < 0.001 and κ 0.735, p < 0.001, respectively) as well as moderate for the right and left internal carotid artery (κ 0.467, p = 0.001 and κ 0.457, p < 0.001, respectively).