Lasting consequences of cigarette smoking on the heart

Abstract

Smoking is associated with increased morbidity and mortality and can harm almost every organ in the body. The risk reduction for cardiovascular diseases with smoking cessation is well documented by numerous clinical studies,¹ but long-term adverse consequences persist. For instance, the risk for cardiovascular complications remains high for ex-smokers, and former heavy smokers have a higher incidence of left ventricular systolic dysfunction, coronary artery and peripheral arterial diseases, and type 2 diabetes. Surprisingly, little is known about the adverse effects that persist in the heart following smoking cessation.

In this issue, Dr. Wüst and colleagues investigated what happens in the heart following smoking cessation on the metabolic, lipidomic, and structural remodeling seen with smoking (Table 1).² It is well established that smoking stimulates cardiovascular remodeling by interdependent pathways involving inflammation, oxidative stress, mitochondrial dysfunction, and hyperlipidemia.³ Using mice, the study conducted by Wüst and colleagues revealed both the reversible and durable effects of smoking on the heart after a cessation period of up to 2 weeks.² Provoked local inflammation and cardiac fibrosis were among the consequences that are not mitigated by short-term cessation. Their findings suggest that a persistent infiltration of macrophages induced by smoking may foster a profibrotic milieu, which increases the risk of a proatherogenic response and cardiovascular complications, such as diastolic dysfunction and arrhythmias.

Quitting smoking may often lead to weight gain, which is a primary concern for contributing to insulin resistance and increasing the inflammatory response and metabolic burden. The study discussed found that smoking exposure causes weight loss and increases long and very long-chain fatty acids in the heart. Upon cessation, mice experienced weight gain and a further increase in their lipid profile. Direct and indirect mechanisms mediated by nicotine or smoking-induced insulin resistance can lead to smoking-induced high lipid profiles. However, weight gain might become an important regulator of metabolism following cessation. Some clinical studies suggest that these effects are typically temporary and tend to reverse after 6 months in humans.⁴ Conversely, there have been reports that suggest a correlation between weight gain and attenuation in the benefit of cessation on the risk of cardiovascular disease.⁵

In addition to the well-known connection between obesity and lipid buildup, Wüst and colleagues discovered evidence of a possible shift in metabolism from fatty acids to glucose after 2 weeks of cessation.² This shift was indicated by higher levels of long-chain fatty acids and increased glycolytic intermediates, suggesting a potential shift toward increased glucose oxidation. Key players in this process were identified by enrichment pathway analysis and included increased glycolysis, pentose phosphate metabolism, and gluconeogenesis. Interestingly, the study revealed that an increase in glucose uptake was potentially achieved by enhanced translocation of the GLUT4 receptor to the membrane. However, since the study did not measure insulin sensitivity or glucose uptake, the overall impact of smoking cessation on insulin homeostasis and glucose metabolism in the heart remains unsettled. Nonetheless, previous research demonstrates that abstaining from smoking for 1–2 weeks without gaining weight or body fat can improve insulin sensitivity.⁶ Additionally, it is worth noting that breakdown of purine and pyrimidine was found to be increased after cessation by Wüst and colleagues,² which is interesting as it corresponds with the metabolic characteristics of hypertrophic cardiomyopathy and other cardiovascular conditions.⁷

On the other hand, smoking cessation induced vascularization and improved mitochondrial respiration and bioenergetics (Table 1). Cessation normalized mitochondrial oxidative phosphorylation capacity to levels seen in the controls, increased the assembly of mitochondrial supercomplexes, and enriched the NAD⁺ pool. These responses were proposed to be adaptive mechanisms that counteract the detrimental effects of smoking on mitochondrial function and oxidative stress upon cessation. Recent research has demonstrated the numerous benefits of expanding the NAD⁺ pool in heart failure.⁸ Beyond its role in redox reactions, NAD⁺ serves as a crucial cofactor for enzymes involved in energy production, metabolism, and DNA repair.

Smoking cessation is key in the management of cardiovascular health. Given the multifaceted and dynamic effects of smoking cessation, monitoring physiological changes following cessation can help in gaining insight into the immediate effects and in identifying optimal support strategies for those endeavoring to quit. While the long-term benefits are noteworthy, it is important to pinpoint crucial mechanisms that can predict or substantially impact risk reduction. This necessitates identifying the reversibility of consequences and the timing involved. As there is no drug-based therapy to reverse fibrosis, an immune-based therapeutic approach early after cessation using CAR T cells may be a viable option.⁹ Noteworthy, the selection of an appropriate therapeutic intervention for smoking cessation is dependent upon the temporal patterns associated with cessation. Given this, it is essential to make a judicious choice of intervention that synchronizes with the timing of the cessation.

There are several limitations to the study by Wüst and colleagues.² Cardiac functional analysis was not performed to determine whether the increase in fibrosis was associated with cardiac stiffness. Moreover, systemic effects of smoking cessation were not measured to better understand the metabolic effects such as insulin sensitivity or glucose tolerance. Finally, although macrophages accumulated in the heart, changes in the overall immune profile following cessation were not determined.

In summary, the study by Wüst and colleagues presents evidence that cardiac fibrosis and macrophage infiltration follow smoking cessation, while metabolic alterations can partially reverse after 2 weeks (Figure 1).² Fibrosis is likely to remain a complicating factor in the long run. Further studies that incorporate repeated measures over a sustained period of time are necessary to investigate this concern.

All authors contributed conceptually to the outline of the editorial commentary. GA provided the first draft. All authors assisted in the writing of the manuscript and creation of the figure. GWB and FAZ edited the final submission.

The author's affirm that they have no conflicts of interest to declare.

GWB was supported in part by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM121334. FAZ was supported by grants from the American University of Beirut Faculty of Medicine (MPP—320145; URB—103949), the Centre National de la Recherche Scientifique (CNRS) (grant number 104230), and the Agence nationale des recherches (ANR) et l'Agence française de développement (AFD) (ANICOV-HF). The content is solely the author's responsibility and does not necessarily represent the official views of the National Institutes of Health.