Cardiovascular diseases (CVD) are the commonest cause of morbidity and mortality worldwide. The commonest underlying mechanism of coronary artery diseases (CAD) is atherosclerosis. Atherosclerotic plaques develop over years leading to a long-term clinically silent coronary obstruction, up to sudden plaque rupture or erosion with subsequent development of acute coronary syndrome (ACS) [1].

Chronic coronary syndromes (CCS), unlike ST-segment elevation myocardial infarction (STEMI), have different predictors of long-term outcomes [2] including left ventricular ejection fraction (LVEF), age, complete revascularization [3], associated acute left ventricular failure, peak troponin level and degree of ST-segment deviation [4]. Also, chronic kidney diseases (CKD) are increasingly becoming a key predictor of cardiac morbidity and mortality [5].

The synergy between percutaneous coronary intervention with TAXUS™ and cardiac surgery (SYNTAX) score was calculated to evaluate both CAD extent and complexity. Moreover, this score could be considered as a strong predictor of major adverse cardiac events (MACE) [6] and cardiovascular death in patients subjected to percutaneous coronary intervention (PCI) [7]. Each coronary lesion could be scored separately using SYNTAX scoring system, and then the total SYNTAX score is achieved by summing all these calculated scores.

The cardio-renal syndrome is the coexistence of both cardiac and renal pathology, and is related to both humoral and neural signaling [8]. Analysis of micro- and macrovascular circulatory parameters could be used for early detection of CVD and related vascular damage. Among these parameters, it was found that renal resistive index (RRI) could be considered as the most reproducible and clinically relevant index of renal hemodynamics and vascular stiffness [9].

RRI is a simple non-invasive renal Doppler Ultrasonography (USG) parameter reflecting renal haemodynamic changes and allowing assessment of renal vascular damage and resistance [10]. Also, RRI was dependent on numerous factors including renal vascular stiffness, age, brady- and tachyarrhythmias, pulse pressure, significant valvular lesions and pathological lesions within renal parenchyma [11].

High RRI was found to be correlated with impaired renal haemodynamics [12]. This could be used to allow accurate prediction of the onset of acute kidney injury and its persistence [13], arterial remodeling and stiffness [9], and adverse CVD events in elderly patients especially those having a hypertensive renal disease [14]. Moreover, in a large cohort enrolling CKD patients, high RRI was significantly associated with increased mortality [15].

Of note, to our knowledge, none of previously published studies assessed the relationship between RRI and CAD. In our study, the aim was to prove the hypothesis that using intra-renal flow parameters may define complex CAD in stable CAD patients by evaluating the association between RRI and extent and complexity of CAD, defined by SYNTAX score.

Data distribution was first assessed using the Kolgormonov-Smirnov test. Then, categorical data were compared based on the chi-square test or Fisher exact test. Continuous variables were also compared according to an unpaired Student’s t-test or Mann–Whitney U-test. Data were expressed as mean $\pm$ standard deviation. The independent predictors of high SYNTAX score in those patients having stable CAD were assessed using the multivariate analysis; including all significant variables based on the p-value of the univariate regression analyses (p 0.05). Receiver operating characteristic curve (ROC) was performed to detect the best cut off value of RRI for defining high SYNTAX score. Two-sided statistical tests were achieved with p-value of 0.05 representing a statistically significant difference. All these analyses were done using SPSS version 20 (SPSS Inc, Armonk, NY, USA).

A total of 214 patients with stable CAD underwent coronary angiography at our institution were enrolled in the present study. Subsequently, out of these 214 patients, 166 patients had low SYNTAX score (SYNTAX $\le$22) (77.6%) and the remaining 48 patients had high SYNTAX score (SYNTAX $>$22) (22.4%).

4.4 Renal Doppler USG Characteristics

Renal USG and Doppler characteristics are shown in Table 3. Regarding USG characteristics, the mean values were 44.08 $\pm$ 3.01 mm for renal width, 104.22 $\pm$ 5.51 mm for renal length, and 14.51 $\pm$ 1.33 mm for renal parenchymal thickness, without significant differences between both groups regarding these parameters (p = 0.91, p = 0.58, and p = 0.95, respectively).

Table 3.Renal USG characteristics of overall population, according to SYNTAX classification.

Variable	All Patients	SYNTAX $\le$22	SYNTAX $>$22	p value
	(n = 214)	(n = 166)	(n = 48)
Renal USG characteristics
Renal width, mm	44.08 $\pm$ 3.01	43.96 $\pm$ 2.14	44.20 $\pm$ 4.12	0.91
Renal length, mm	104.22 $\pm$ 5.51	103.18 $\pm$ 4.79	105.26 $\pm$ 6.52	0.58
Renal parenchymal thickness, mm	14.51 $\pm$ 1.33	14.48 $\pm$ 1.22	14.54 $\pm$ 1.57	0.95
Aorta PS, cm/s	65.57 $\pm$ 23.64	66.96 $\pm$ 24.97	59.51 $\pm$ 15.78	0.12
PSV, m/s	57.46 $\pm$ 27.28	57.48 $\pm$ 27.47	57.36 $\pm$ 27.17	0.99
RPI	1.37 $\pm$ 0.40	1.38 $\pm$ 0.41	1.34 $\pm$ 0.38	0.79
RRI	0.632 $\pm$ 0.076	0.614 $\pm$ 0.072	0.699 $\pm$ 0.047	0.001

PS, peak systolic; PSV, peak systolic velocity; RPI, renal pulsatile index; RRI, renal resisitive index; USG, ultrasonography; SYNTAX, percutaneous coronary intervention with TAXUS™ and cardiac surgery.

Regarding renal Doppler characteristics, there were no significant differences between two SYNTAX groups regarding mean values of PSV (57.48 $\pm$ 27.47 vs. 57.36 $\pm$ 27.17 m/s, p = 0.99) and RPI (1.38 $\pm$ 0.41 vs. 1.34 $\pm$ 0.38, p = 0.79). However, in comparison with low SYNTAX score group, mean RRI value was significantly higher in patients included in the high SYNTAX score group (0.699 $\pm$ 0.047 vs. 0.614 $\pm$ 0.072, p 0.001).

ROC statistical analyses (Table 4) showed that RRI $>$0.655 (sensitivity of 80%, specificity of 73.6%) was the best cut-off value for predicting high SYNTAX score (SYNTAX $>$22) in patients with stable CAD (Fig. 1).

Table 4.Sensitivity and specificity for RRI to predict high SYNTAX score (SYNTAX $\mathrm{>}$22) in patients with stable CAD.

Variable	AUC	p-value	95% CI	Cut off	Sensitivity	Specificity
RRI	0.834	0.001	0.756–0.912	$>$ 0.655	80.0%	73.6%

RRI, renal resistive index; SYNTAX, percutaneous coronary intervention with TAXUS™ and cardiac surgery; CAD, coronary artery disease; AUC, area under curve.

Fig. 1.

ROC curve of RRI for prediction of high syntax score (SYNTAX $\mathrm{>}$22). RRI $>$0.655 (sensitivity of 80%, specificity of 73.6%). SYNTAX, percutaneous coronary intervention with TAXUS™ and cardiac surgery; AUC, area under curve; RRI, renal resistive index; ROC, receiver operating curve.

The main findings of our study were: (1) in stable CAD patients, diabetes mellitus, dyslipidemia, and smoking were more frequent in those with high SYNTAX score group (SYNTAX $>$22) compared to others with low SYNTAX score (SYNTAX $\le$22), (2) Moreover, left main and multi-vessel CAD were more pronounced in high SYNTAX score patients (SYNTAX $>$22) along with higher Gensini score, compared to those with lower SYNTAX score (SYNTAX $\le$22), (3) RRI, as determined by the non-invasive renal Doppler study, was significantly higher in the patients with more complex CAD than in those with lower CAD complexity, and (4) RRI along with diabetes mellitus, LDL-C levels, multivessel CAD and Gensini score could be considered as strong independent predictors of complex CAD with higher SYNTAX score (SYNTAX $>$22) in stable CAD patients.

Atherosclerosis is a chronic immune-inflammatory and fibro-proliferative disease with a systemic and progressive behaviour. It is heterogeneously distributed in coronary plaques and frequently affects peripheral vasculature as renal arteries in addition to aorta and coronary arteries. In coronary arteries, atherosclerosis is characterized by its fatty streaks in childhood. However, in adulthood, fibrous plaques are more noted with more complex and advanced coronary lesions [25]. Concurrently, the kidneys are characterized by their significant arterial vascular structure, and also are affected by atherosclerosis lie coronary arteries where it leads to both anatomical and functional effects in the kidneys [26].

Our study included 214 patients with stable CAD who had been admitted to our catheterization laboratory to perform coronary angiography. According to complexity of atherosclerotic coronary lesions defined by the SYNTAX score, these patients were subsequently divided into those with SYNTAX score $\le$22 and others with a higher SYNTAX score $>$22. The role of old age, male gender, smoking habit, diabetes mellitus and obesity as major determinants of complex CAD lesions has been discussed extensively before, where the publication stated by the Framingham Heart study and a series of landmark studies reported a causal relationship with atherosclerosis [27].

Within the same context, the present study reported a higher frequency of smoking (64.6% vs. 44%, p = 0.01) and diabetes mellitus (64.6% vs. 41.6%, p = 0.005) among patients with stable CAD and having complex coronary lesions (SYNTAX $>$22) compared to those with less severe coronary lesions (SYNTAX $\le$22). This could be attributed to the fact that smoking affects atherosclerosis phases; from endothelial dysfunction to adverse clinical events [28]. Also, in diabetics, it was stated that hyperglycemia, insulin resistance and free fatty acid release could lead to a significantly increased oxidative stress, and therefore atherosclerosis acceleration [29]. Moreover, dyslipidemia was more frequent in stable CAD patients included in this study with a higher SYNTAX score.

RRI is a non-invasive renal Doppler modality used to assess renal hemodynamics. Moreover, RRI could be considered as a result of complex haemodynamic interactions involving both the kidneys and the systemic vasculature, and most of those interactions are not entirely understood yet. Kintis et al. [30] stated that RRI provides also a prognostic information regarding the systemic vasculature and could be considered as a promising marker for vascular damage, where high RRI could result in adverse clinical outcomes, especially in elderly, hypertensive, and diabetic patients.

This strong association between elevated RRI and systemic vascular damage was reported in many other previous studies where Prejbisz et al. [31] reported that a higher RRI was noticed in patients having a truly resistant hypertension than those with a well controlled systemic hypertension (0.62 $\pm$ 0.05 vs. 0.60 $\pm$ 0.05, p 0.05). Also, RRI revealed a significant correlation with both pulse and ambulatory blood pressure values, fasting glucose levels and E/e’ ratio [31]. It was noted that the metabolic effects of RRI could be illustrated in patients with type 2 diabetes mellitus, where dynamic values; RRI changes after sublingual nitrate, could predict the microalbuminuria onset [32]. Also, Geraci et al. [33] stated that RRI values were greatly correlated with both the extent of carotid atherosclerosis and carotid intima-media thickness (IMT) assessed in hypertensive patients.

More recently, Geraci et al. [34] reported that the Doppler-based intra-renal flow parameters were greatly associated with severity of atherosclerotic lesions assessed in coronary angiography, but only noted among those patients having less pronounced atherosclerosis. Of note, this significant correlation was found to be valid for RPI, but not RRI, which needs further explanations. On this basis, there are no sufficient studies discussing the correlation between extent and severity of atherosclerotic CAD and RRI, and thus, we hypothesized in this study that RRI values determined by renal Doppler studies could be used to investigate renal vasculature and correlating it with the atherosclerotic CAD severity to assess the RRI value to predict its progression.

Accordingly, the present study shed light on the relationship between RRI and the complex coronary lesions in patients with stable atherosclerotic CAD. It was also found that RRI was higher in patients having more complex coronary lesions (SYNTAX $>$22) than those having less severe coronary lesions (SYNTAX $\le$22) (0.699 $\pm$ 0.047 vs. 0.614 $\pm$ 0.072, p 0.001). This finding was in accordance with Higuchi et al. [35] that reported a significant correlation between higher RRI and patients having multi-vessel diseases than those with only single or double vessel diseases (p 0.01). Within the same context, Alan et al. [36] reported that RRI values were also higher in CAD patients with severe lesions compared to those with mild lesions (p 0.001).

However, our results came in contrast with Demirtaş and Bulut who reported that RRI in the low-risk ACS patients (mean SYNTAX Score 12) was 0.73 $\pm$ 0.07 while in high risk patients (mean SYNTAX Score $\ge$12) was 0.76 $\pm$ 0.08 without significant differences between both groups. Higher RRI observed in this high risk group may be related to acute stress, however, non-significant difference could be attributed to difficult Doppler assessment of the kidneys due to retroperitoneal location, difficult assessment in obese patients and limited efficacy of shear wave elastography (SWE) using the acoustic radiation force impulse imaging modality in the kidneys located deeper than 5 cm [37]. Of note, these results could be considered as novel ones as the study exclusively included stable CAD patients; not ACS patients, without renal impairment (eGFR $\ge$50 mL/min/1.73 m${}^2$). Thus, the current study highlights the valuable clinical impacts of RRI regardless of the kidney status, which could greatly affect the RRI results.

The present study has a great clinical implication where it documents that RRI could be considered as a novel strong independent predictor of high SYNTAX score in stable atherosclerotic CAD, besides other traditional predictors as diabetes mellitus, LDL-C level, multi-vessel CAD, and Gensini score. In line with these findings, the cohort study stated by Pearce et al. [14] revealed a significant association between Doppler renal parameters; including RRI and RPI, and adverse cardiovascular events. Also, Akgul et al. [38] proved a relationship between RRI and both cardiac risk factors and carotid IMT. It was stated that a mild renal dysfunction has been also reported to be a strong independent risk factor for cardiovascular mortality, even after proper controlling of other atherosclerotic risk factors [39].

The main underlying mechanisms illustrating the higher SYNTAX score associated with high RRI values are still uncertain. However, this could be attributed to a histological study showing that the reno-vascular atherosclerosis is considered as independent risk factor for an increased RRI. Moreover, atherosclerosis is a systemic process, and its main pathophysiology is nearly the same in all involved patients [40]. Also, recent studies including hypertensive patients documented a significant correlation between arterial stiffness index [41], central pulse pressure, aortic stiffness [42] and RRI. Accordingly, the RRI could be a novel indicator of a systemic vascular injury rather than only a renal vascular damage. Moreover, Wybraniec et al. [24] stated that the mechanism underlying this predictive role of RRI could be attributed to its correlation with both vascular remodelling (stiffness) and vascular sympathetic tone (renal artery constriction). It was stated that a higher sympathetic tone within renal arcuate and interlobular arteries could lead to both lower EDV and higher RRI values in high risk atherosclerotic CAD patients [24]. The present study has a unique design as it compensated for intrarenal flow variations by excluding those patients having valvular heart disease that could be considered as a significant determinant of RRI and also adverse long-term outcomes.

Alan et al. [36] analysed the diagnostic clinical performance of RRI values in ROC analyses to differentiate CAD severity according to Gensini score. They found that the best cut-off value was 0.605 with sensitivity of 80.60% and specificity of 66.70% [36]. Furthermore, Calabia et al. [43] found high specificity and sensitivity values for RRI in determining arterial vascular stiffness. In this study, the best cut-off RRI value to differentiate patients with a high SYNTAX score was $>$0.655 with sensitivity of 80% and specificity of 73.6%. Accordingly, we suggest that RRI values determined by renal Doppler studies may provide useful information about the progression of CAD before being irreversible with a high degree of complexity, and thus allowing early treatment of CAD. These findings were supported by Rosławiecka et al. [44] who stated that patients having renal artery stenosis with a concomitant atherosclerotic lesion ($>$30% stenosis) in the contralateral renal artery are associated with adverse cardiovascular events.

The present study had some limitations. First, it is a single-centre study including small number of certain patients with stable CAD. Thus, multicentre studies including more patients could have more significant data and results to investigate the correlation between increased RRI and cardiovascular mortality and adverse events. Second, RRI is limited by its dependence on numerous variables altering the intra-renal hemodynamics. However, patients with severe valvular lesions of any kind, high pulse pressure, tachy- and bradyarrhythmias were excluded from this study. Third, this study didn’t evaluate the potential effects of drugs taken by some patients prior to RRI assessment. Lastly, the measurements of Doppler parameters as PSV and EDV and their derivatives are influenced by inter- and intra-observer variability. Thus, measurements were repeated in kidneys using the arithmetic mean of these measurements.

Atherosclerosis is commonly associated with the affection of both coronary and renal vasculatures. In patients with stable atherosclerotic CAD, the RRI is significantly associated with both angiographic extent and complexity of CAD; and not only a specific marker for renal vascular damage. Thus, this RRI could be considered as a diagnostic modality which is easily accessible to improve the stratification of cardiovascular risk and provide additional prognostic information in stable CAD patients referred to invasive procedures.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

HR designed the research study and analyzed data. AT has made substantial contributions to data acquisition, and data analysis and interpretation. HR and AT revised the article critically for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was carried out in adherence to the principles of the Declaration of Helsinki on Biomedical Research Involving Human Subjects. The Ethics Committee of Zagazig university approved the study protocol (ZU-IRB #62/5). All study population already gave written informed consents prior to study participation.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.