The high prevalence and mortality of cardiovascular diseases (CVD) highlights the urgent need to implement tools to better stratify cardiovascular risks, to identify patients at high risk, and to diagnose and treat CVD in early stages. One of these tools are cardiovascular biomarkers, which can detect CVD in a subclinical phase with good accuracy, thereby improving the prevention of events and the epidemiological scenario.^{1 , 2}

Some of the main biomarkers related to vascular structure and function are intima-media thickness (IMT), the presence of carotid plaques, pulse wave velocity (PWV), and the ankle-brachial index (ABI).² In addition, other cardiovascular biomarkers are used to identify target-organ damage (TOD), such as left ventricular hypertrophy, elevated serum creatinine levels, increased albumin excretion, and reduced glomerular filtration rate.^{3 , 4}

PWV, a vascular damage biomarker used to assess arterial stiffness, is considered a strong and independent marker of TOD and adverse events.⁵ PWV is also a predictor of all-cause mortality, indicating the patient’s actual risk.⁶ Each one meter per second rise in PWV leads to an increases by 14% in the risk of adverse events and by 15% in the cardiovascular risk and all-cause mortality.⁶ Among its advantages, PWV is non-invasive, easily performed, relatively inexpensive, and widely validated method² with clearly established reference values.^{7 , 8} Despite this evidence, PWV remains underused in clinical practice, and few studies have analyzed its relationship with other biomarkers, specially using oscilometric method. Thus, the objective of this study was to investigate the relationship between PWV and other biomarkers of cardiovascular structural changes in patients with cardiovascular risk factors.

In total, 355 individuals with a mean age of 56.1 (±14.8) years participated in this study. Most of them had dyslipidemia and/or arterial hypertension, 148 (41.7%) were overweight and 130 (36.6%) were obese ( Table 1 ).

Table 1

Variables		Mean (SD) / Median (25%-75%) / n (%)
Age		56.1 (±14.8)
BMI		28.7 (±4.9)
SBPc		113 (107-123)
Alx		21.5 (±13.4)
PWV		8.2 (±2)
Sex
Male		181 (51%)
Female		174 (49%)
Marital status
With partner		251 (70.7%)
Without partner		102 (28.7%)
CVRF
Overweight		148 (41.7%)
Obesity		130 (36.6%)
Tobacco smoking		12 (3.4%)
Diagnosis
Dyslipidemia		306 (86.2%)
Arterial hypertension		283 (79.7%)
Diabetes mellitus		65 (18.3%)
Pre-hypertension		47 (13.2%)

Aix: augmentation index; BMI: body mass index; CVRF: cardiovascular risk factors; PWV: pulse wave velocity; SBPc: central systolic blood pressure.

A moderate and positive correlation was found between PWV and IMT; and positive and weak correlations were identified between PWV and LVST, and between LVPWT and LAD ( Table 2 ).

Table 2

		IMT (n=178)	LVST (n=313)	LVPWT (n=312)	LAD (n=312)
PWV	r	0.310†	0.191†	0.215†	0.181‡
	p	<0.001*	0.001*	<0.001*	0.001*

*p < 0.05.^†Spearman’s rank-order correlation;^‡Pearson product-moment correlation. IMT: intima-media thickness; LAD: left atrial diameter; LVPWT: left ventricular posterior wall thickness; LVST: left ventricular septal thickness; PWV: pulse wave velocity.

IMT was associated with PWV adjusted by age and peripheral systolic pressure (p=0.0004), such that IMT greater than 1 mm increased by 3.94 the chance of having PWV above 10 m/s ( Tables 3 and 4 ).

Table 3

Variables	OR	95%CI (OR)	p
LVST	2.49	1.38 – 4.49	0.003*
IMT	3.94	1.53 – 10.15	0.004*
LVPWT	2.34	1.29 – 4.22	0.005*
LAD	2.55	1.18 – 5.49	0.017*

Linear bivariate regression analysis. CI: confidence interval; IMT: intima-media thickness; LAD: left atrial diameter; LVPWT: left ventricular posterior wall thickness; LVST: left ventricular septal thickness; OR, odds ratio; * p < 0.05.

Table 4

Variables	Adjusted OR	95%CI (OR)	p	Adjusted OR*	95%CI (OR)	p
LVST	1.64	0.59-4.5	0.340	-	-	-
IMT	3.94	1.53- 10.15	0.004	6.86	1.78-26.45	<0.001
LVPWT	1.69	0.64-4.49	0.294	-	-	-
LAD	1.34	0.27-6.80	0.705	-	-	-

Multiple regression analysis. CI: confidence interval; IMT: intima-media thickness; LAD: left atrial diameter; LVPWT: left ventricular posterior wall thickness; LVST: left ventricular septal thickness; OR, odds ratio; * p < 0.05.

PWV was significantly higher in individuals with LVH, higher IMT, in those with carotid plaque, in those with stenosis equal to or greater than 50%, and in those with TOD ( Table 5 ).

Table 5

Variable	Group	n	PWV	CI	p
LVH †	No	212	7.6	7.55 - 8.03	<0.0001*
	Yes	105	9.1	8.74 – 9.53
IMT ‡	≤ 1 mm	152	8.07	7.79 - 8.35	0.006
	> 1 mm	26	9.12	8.32 - 9.90
Presence of plaque ‡	No	82	7.44	7.14 - 7.75	<0.0001*
	Yes	172	9.09	8.83 - 9.35
Plaque size ‡	< 50%	146	8.92	8.64 - 9.20	0.003
	≥ 50%	25	10.0	9.42 - 10.63
Target organ damage** ,‡	No	118	6.9	6.62 - 7.12	<0.0001*
	Yes	237	8.9	8.69 - 9.17

CI: confidence interval; IMT: intima-media thickness; LVH: left ventricular hypertrophy; PWV: pulse wave velocity. *p < 0.05.^†Mann-Whitney test.^‡t-test for independent samples. ** IMT>1mm, presence of plaque, LVH or PWV > 10 m/s.

In the present study, PWV was correlated with all biomarkers evaluated, and associated with IMT even when adjusted for age and peripheral systolic pressure. The chance of having PWV above 10 m/s increases by 3.94 times in the presence of IMT greater than 1 mm. PWV have had a linear increment with the presence and size of atheroma plaque and with the presence of TOD. These findings are in accordance with previously published studies,^{2 , 20 , 21} and reinforce the value of this biomarker and its ability to identify early cardiovascular damage, in addition to its excellent cost-effectiveness.

The correlation of PWV with echocardiographic parameters observed in the present study may be explained by the fact that arterial stiffness increases the SBP, and, consequently, the reflected wave returns early and arrives in systole instead of diastole, increasing the post-load of the left ventricle. This increased workload imposed on the myocardium promotes cardiac myocyte hypertrophy, resulting in ventricular hypertrophy.^{22 - 24}

LVH, which may be identified by an increase in left ventricular wall thickness on echocardiogram, is correlated with PWV, and PWV values are significantly higher in individuals with LVH.^{22 , 23} The increase in the load imposed on the left ventricle is one of the main causes of cardiovascular events related to CBP.²⁵

Many studies show not only a correlation^{26 - 28} but also an association between arterial stiffness and LVH.^{22 , 23 , 29 - 32} Therefore, increased arterial stiffness may be used as a predictor of LVH, contributing to the prevention and diagnosis of this condition.²³

In our study, PWV was not independently associated with LVST, LVPWT, or LAD, perhaps because the association analysis was not performed between hypertrophy itself and PWV, as in the studies cited, but rather between echocardiographic parameters and PWV. Furthermore, one of the studies cited²² used electrocardiographic and not echocardiographic findings, and most studies performed this association analysis based on the left ventricular mass index.^{23 , 28 , 30 , 32}

The relationship between the increases in arterial stiffness and the increases in IMT can be explained by the pathophysiology of arterial stiffness, which encompasses changes in the extracellular matrix of the middle layer (tunica media), including elastin breakdown, collagen deposition, and reticulation.^{24 , 33} Those morphological changes are also related to vascular aging.³⁴

Increased IMT is also associated with the presence of risk factors for arteriosclerosis; and age, arterial blood pressure, serum lipids, and fasting blood glucose levels are all independent predictors of carotid atherosclerosis.³⁵ Increased IMT is one of the first subclinical manifestations of arteriosclerosis.³⁶ The presence of multiple cardiovascular risk factors is independently associated with increases in IMT and decreases in arterial compliance.³⁷

The correlation³⁸ and association of IMT with PWV was also previously reported in an elderly population.^{38 , 39}

The assessment of IMT and PWV can improve cardiovascular risk reclassification, and these biomarkers may be used to identify subclinical TOD.⁴⁰ The combination of these biomarkers increases the predictive power of cardiovascular events among elderly people, providing additional and important clinical information.⁴¹

Significantly higher PWV values were also identified in individuals with stenosis equal to or greater than 50% in the present study. Higher PWV values were also significantly associated with the presence of carotid plaques.³⁶ Furthermore, decreased carotid elasticity is associated with the presence of plaques and the risk of stroke.⁴²

The combined assessment of IMT and the presence of plaques improves the prediction of cardiovascular risk, and the quantitative evaluation of plaques further increases the predictive sensitivity.⁴³ Moreover, femoral carotid PWV and the number of atheroma plaques are significantly and independently associated with cardiovascular death and can improve the identification of individuals at high cardiovascular risk.⁴⁴

In addition to the associations between PWV and biomarkers, the significant difference in PWV found between study subjects with and without TOD highlights the capacity of PWV to early identify the damage. Arterial stiffness is an independent predictor of mortality for both diabetics and the general population, and it is related to TOD development and progression.⁴⁵

Arterial stiffness, assessed by PWV, is independently associated with the presence of subclinical TOD, including coronary artery calcification, reduced ankle-brachial index (peripheral arterial disease), and white matter hyperintensity (cerebral arterial disease).⁴⁶

When TOD is present and is not identified, many patients are wrongly classified as medium-to-low risk when they are actually at high cardiovascular risk.⁴⁷

Diagnostic tools must be improved and established for the early identification of increased risk, to prevent the onset of TOD and its complications. The appropriate identification of low-risk individuals is equally as important to avoid unnecessary treatments and their concomitant side effects.⁴⁸ The use of vascular biomarkers is a cost-effective, value-added method of improving the identification of individuals at high cardiovascular risk, thereby facilitating the prevention of CVD.⁴⁴

The limitations of this study are as follows: when diagnosis of diabetes mellitus, dyslipidemia, and arterial hypertension was not available in the medical records, the diagnosis was made during the study, on an ad hoc basis, which may have under- or overestimated the frequencies of those diseases. Some exposure variables were missing from the medical records. In addition, we cannot ensure that all patients underwent carotid Doppler and echocardiography at the same clinic and with the same evaluator. Hypertrophy could not be detected by the ventricular mass index, since this information was not available in the medical records.

The medical records and diagnostic criteria were reviewed with scientific rigor, and the data were reviewed by two researchers and subsequently crosschecked. All these procedures should suffice to validate the findings.

The present study highlights the importance of using PWV for the early detection of arterial stiffness and TOD, focusing on increases in IMT, the presence of carotid plaques, and LVH. Overall, the use of PWV may optimize the stratification of cardiovascular risk to facilitate early intervention and prevent CVD and its complications.

PWV was significantly correlated with IMT and echocardiographic parameters and was associated with IMT. Furthermore, an IMT greater than 1 mm increased the chance of having PWV above 10 m/s by 3.94 times. PWV was significantly higher in individuals with LVH, IMT greater than 1 mm, in those with stenosis equal to or greater than 50%, and in those with TOD.