The main findings of the current study were the identification of different vascular waveforms in the female and male SG when properly compared with their same sex CG. A drop in impedance was detected in the territory of the OA and an increase in impedance in the MCA in the female SG compared with the CG. However, there were no significant differences between the male SG and CG in the vascular waveforms. These findings characterise distinct patterns according to sex.
Sex is a non-modifiable risk factor for vascular diseases2 that had historically been undervalued until recently. Individual factors involving sex and the perception that each one can require different management diagnosis and therapeutics occurred only in the early 2000s, when the ‘one size fits all’ approach started to become invalid10. Sex-specific differences in heart diseases can occur because women have sex-specific risk factors related to pregnancy disorders, gestational diabetes, hypertension, preeclampsia, and endocrine changes10. From the perspective of vascular diseases, sex differences have profound implications for effective stroke prevention and treatment. This is based on the multifactorial nature of anatomic, genetic, and sex hormonal factors. Pre-menopausal women seem less vulnerable to stroke than men of similar ages, but after menopause, there is an increase in stroke among women11. When associated with sex, smoking can modify this epidemiology of vascular diseases1,2. Prolonged smoking, besides being one of the most relevant modifiable risk factors2, also appears to be the most specific risk factors associated with sex in CVD, causing more harm in women than in men10 and greater risk of haemorrhagic stroke in women than men, independently of differences in other risk factors4.
We did not identify studies in the literature that analysed the Doppler waveforms of both the OA and the MCA by comparing groups of smokers and non-smokers according to sex. Hence, there is not a similar study to which we can compare our data. There is a published study that compared the Doppler parameters of the OA in chronic smokers in relation to a control group of non-smokers, but the researchers used mixed-sex groups12. Their smoker group comprised 49 (27 male, 22 female) cigarette smokers (≥ 2 years and ≥ 10 cigarettes a day), and their control group was 40 healthy non-smokers. The findings were higher RI and lower EDV in the OA in chronic smokers compared with the control group, which is not in accordance with our study, where we identified lower RI and no significant difference in the EDV in the group of women, and no differences in men. With regard to the MCA Doppler parameters, researchers have assessed the reactivity of the artery by comparing the findings before and after smoking in the same group, an approach that limits the comparative analysis with our data13–15.
Although the mechanisms that cause vascular diseases have not yet been fully elucidated3, the inflammation and damage to endothelium5, the decrease in the release of nitric oxide in response to shear stress and stretch of vasculature16, activation of vascular remodelling17, and an increase in arterial wall stiffness18 have been implicated. These events cause pathological adaptive changes in the microcirculation and are primordial lesions that increase risks for future macrovascular events and consequent damage to final organs such as the heart and brain5. Changes in the arterial waveform of smokers may represent the preclinical phase of vascular disease before atherosclerosis, which manifests itself in more advanced stages of vascular impairment5.
Our findings suggest that in the case of cigarette consumption, men may have better adaptation in the microcirculation than women, probably because of oestradiol and progesterone hormones present in women. In relation to PR, which represents the index of the morphology waveform, the exact mechanism of its modification in the female SG is still unclear. Its increase has been correlated to hyperperfusion19 or to waveform change caused by the sum of the incident wave travelling towards the periphery and the early return of the reflected wave returning from the periphery reflecting on the systole and raising P218. This increased reflection is caused by arterial stiffness and increased local vascular tone, which cause repetitive reflections of the waves along the systemic arterial tree between the heart and the arteries studied20. Therefore, the higher PR may reflect local arterial preclinical disease and its possibility for future progression to atherosclerosis21, early changes in microcirculatory compliance causing downstream hyperperfusion, or both. In female smokers, PR is increased, which may suggest arterial stiffness and distal hyperperfusion in women.
Of note, only the female SG presented elevated RI and PI in the MCA in relation to the CG. The increase in PI in the MCA has been correlated with impaired cerebral perfusion due to small vessel disease22 and worse cognitive performance related to microangiopathy and inflammation.23 In addition, PI in the MCA assessed by transcranial Doppler is well correlated with a variety of manifestations observed by magnetic resonance imaging, such as periventricular hyperintensity, deep white matter hyperintensity, lacunar disease, and dot hyperintensity; this factor strengthens the hypothesis that this index reflects the degree of resistance downstream in the intracranial circulation and that its values are high in small vessel diseases6.
Both vasospasm in basal cerebral arteries and dilation of peripheral vessels or even a combined effect of both have been postulated as actions of cigarette components15. Only female smokers showed a statistically significant increase in RI and PI of the MCA. Besides, an increase in EDV is regarded as an indirect sign of dilation of smaller vessels, associated with a decrease in peripheral resistance14; thus, its reduction in the female SG is yet another sign of reduction in cerebral peripheral perfusion.
Regarding both arteries studied, the OA showed an opposite change in waveform to the MCA. The reasons for these findings may be due to the difference in calibre between these vessels, different mechanisms of self-regulation, or complex interactions between these vessels24. Although the OA has been used to evaluate cerebral circulation25, we found a different waveform pattern in relation to the MCA because the OA may attempt to compensate for the cerebral blood flow through increased perfusion or vasodilation. The waveform changes in the OA may reflect a compensatory mechanism known as ‘inverse steal’ of this vessel, characterised by increased blood flow in this vessel in an attempt to increase cerebral blood flow when it is reduced due to vasoconstriction of local arterioles26. Thus, the altered OA and MCA waveforms in female smokers may be due in part to vasospasm of conductive cerebral vessels as well as vasoconstriction of small cerebral vessels.
The main limitation of this study, as in all studies using Doppler, is the impossibility to evaluate arterial diameter, a factor that limits the ability to clarify the exact mechanism that causes changes in the waveform. Thus, it is not possible to determine whether the biggest changes occur in the conductive vessel by vasospasm or in the downstream microcirculation, or whether there is a combined effect of both.