A recent article published in Nature’s Hypertension Research discussed the effects of smoking cessation on vascular endothelial function.
Study: Smoking cessation and vascular endothelial function. Image Credit: nookniicks/Shutterstock.com
The vascular endothelium represents a monolayer of endothelial cells that envelops the innermost surfaces of arteries, veins, cardiac lumina, and lymphatic vessels.
These endothelial cells are responsible for the secretion of various vasodilatory factors, notably nitric oxide (NO), a pivotal component in the regulation of vascular endothelium-dependent dilation (EDD) or relaxation. Disruption of this mechanism is a critical factor in the pathogenesis of atherosclerosis.
In the absence of appropriate intervention, the gradual progression of atherosclerosis, characterized by the accumulation of plaque within arterial walls, signifies the initial stage of vascular endothelial dysfunction. Over time, this pathological process culminates in a spectrum of cardiovascular events, including myocardial infarction, stroke, and heart failure.
Epidemiological investigations have unveiled a robust association between all cardiovascular events, with particular emphasis on atherosclerosis, and both the extent and duration of smoking.
In addition to serving as an independent risk factor for atherosclerosis and compromised vascular endothelial function, smoking disrupts the equilibrium of low- and high-density lipoprotein (LDL/HDL) ratios and elevates circulating levels of blood catecholamines and fibrinogen.
Numerous other factors can instigate endothelial dysfunction, including obesity, advanced age, and sedentary lifestyle, among others. Therefore, timely interventions encompassing pharmacotherapy, supplementation, and lifestyle modifications may offer avenues for amelioration.
Similarly, smoking cessation is expected to contribute to the improvement of endothelial dysfunction, although the existing evidence to substantiate its positive effects is limited.
One study has demonstrated that smoking cessation led to a 24% reduction in cardiovascular mortality among female smokers. However, the question of whether smoking cessation can ameliorate advanced atherosclerosis remains unresolved.
About the study
The present study focused on the mechanism(s) that induced vascular endothelial dysfunction during smoking and whether smoking cessation improved it.
Previous studies have found that smoking impairs vascular endothelial function by decreasing NO bioavailability induced by oxidative stress and inflammation. However, scientific evidence supporting that smoking cessation has a positive effect (only) on vascular endothelial function is scarce.
One well-recognized in vivo physiological assessment of EDD is intra-arterial infusion of acetylcholine, which evokes EDD measurable by ultrasound.
Likewise, flow-mediated dilation (FMD) measures the vascular endothelial function of the brachial artery utilizing ultrasound.
It requires inducing arterial dilation during PORH, achieved through inflating a pneumatic pressure cuff around the arm to supra systolic blood pressure for 5 minutes.
In the context of microvasculature, PORH is measured as reactive hyperemia index (RHI), and this method uses a digital pulse waveform to measure EDD.
In addition, there are biomarkers to assess endothelial function/dysfunction. These are nitrate/nitrite, NO, von Willebrand factor (vWF), cellular adhesion molecules (CAMs), including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), endothelin-1 and activity of endothelial NOS (eNOS).
Multiple studies, conducted using experimental animal models and human subjects, have consistently demonstrated impaired endothelium-dependent dilation (EDD) in individuals who smoke. In one particular study, the author observed that administering acetylcholine (an NO agonist) in the forearm arteries impaired endothelial function in smokers but not nonsmokers.
These findings are consistent with another study that reported the pre-administration of NG-monomethyl-L-arginine acetate, an inhibitor of nitric oxide synthase (NOS), which abolished the difference in acetylcholine-induced EDD between smokers and nonsmokers. Additionally, in a different study where researchers induced vasodilation through reactive hyperemia, flow-mediated dilation (FMD) in forearm arteries decreased in smokers, with a more pronounced effect as the amount of smoking increased.
Regarding the underlying mechanisms, the author noted that smoking induces a cascade of reactive oxygen species (ROS) production due to increased nitric oxide (NO) scavenging. This, in turn, leads to oxidative stress conditions, ultimately resulting in vascular endothelial dysfunction. Another observed effect is that ROS present in cigarette smoke reduces blood ascorbic acid levels and elevates oxidative stress markers in the blood. These oxidative stress conditions, whether direct or indirect, play a role in the development of atherosclerosis.
One of the intracellular signaling pathways activated by smoking is Rho-associated kinase (ROCK), and its activity significantly correlates with FMD in smokers. ROCK activation diminishes endothelial nitric oxide synthase (eNOS) activity by destabilizing eNOS mRNA and inhibiting Akt phosphorylation, initiating a detrimental cycle that exacerbates vascular endothelial damage. It's important to note that the onset of atherosclerosis reinforces itself and exacerbates the condition.
Furthermore, the author highlighted that between 1998 and 2022, spanning over two decades, only 23 studies investigated the effects of smoking cessation on vascular endothelial function in smokers. Interestingly, not all of these studies demonstrated the benefits of smoking cessation on vascular endothelial function.
For instance, Johnson et al. examined data from 1,504 cigarette smokers and found that their flow-mediated dilation (FMD) improved within a year of smoking cessation. On the other hand, Mah et al. conducted two studies among healthy young smokers. The first study revealed that quitting smoking for seven days and 24 hours did not improve FMD, while the second showed that smoking cessation, in combination with γ-tocopherol supplementation, improved FMD.
In total, 15 studies evaluated the effects of smoking cessation on endothelial function using physiological methods such as FMD and RHI (Reactive Hyperemia Index). Out of these, 12 reported that smoking cessation improved RHI, FMD, or the response to vasoactive agents, while the remaining three showed no effect on FMD or RHI.
Eight studies utilized biomarkers for similar assessments, of which three found no effects of smoking cessation on biomarkers like ICAM-1, NO, vvWF, EPCs, EMPs, and eNOS activity. Importantly, none of them reported that smoking cessation worsened endothelial function.
Another intriguing observation in the present study was that two studies indicated smoking cessation improved vascular function among e-cigarette users who had transitioned to nicotine replacement therapy.
The current study showed that studies investigating the association of smoking cessation with vascular endothelial function were overwhelmingly small. Moreover, their findings were inconsistent, and not all found positive effects of smoking cessation on vascular endothelial function.
Thus, there is a need for doing large-scale clinical trials of appropriate study design among healthy and diseased subjects (e.g., with advanced atherosclerosis) using different smoking cessation methods and short- to long-term follow-up periods.
These studies should investigate whether the smoking amount, duration of cessation, and method for quitting smoking affect endothelial function and elucidate other mechanisms by which smoking might induce endothelial dysfunction.