This editorial refers to ‘Chronic venous insufficiency, cardiovascular disease, and mortality: a population study’, by J.H. Prochaska et al., https://doi.org/10.1093/eurheartj/ehab495.
During evaluation of varicose veins, my patients frequently ask me whether the ‘bad circulation’ in the legs indicates that they are going to develop heart disease. My typical answer is reassuring, explaining that the veins in the leg are different from the arteries in the heart that cause heart attacks. I encourage heart-healthy walking and diet but not additional concern about cardiovascular risk. The manuscript by Prochaska and colleagues in this issue of the European Heart Journal challenges our conventional thinking about the separation of venous and arterial disease and has important clinical implications.1
Chronic venous disease has a high global prevalence, with diverse manifestations ranging from telangiectasia to varicose veins and, in advanced cases, ulcerations.2 The underlying pathophysiology involves venous hypertension in the legs induced by several potential factors including venous valve dysfunction leading to retrograde blood flow, calf muscle pump dysfunction, and systemic haemodynamic changes including in obesity and right heart failure. Diagnosis of chronic venous disease relies on typical physical examination features that are included in the Clinical, Etiology, Anatomic, Pathophysiology (CEAP) classification system: telangiectasia or reticular veins, varicose veins, oedema, pigmentation or lipodermatosclerosis, and ulceration. Treatment involves compression therapy for all and interventional therapy in selected patients. Prior studies have explored the risk factors for chronic venous disease that include age, obesity, female sex, smoking, family history, and prior venous thrombosis.3–5
The presence of shared risk factors for chronic venous disease and cardiovascular disease spurred the epidemiological investigation by Prochaska and colleagues from the Gutenberg Heart Study.1 In 12 423 adult participants in the population-based cohort study, the investigators classified chronic venous disease using the CEAP system by assessing lower extremity appearance on physical examination and digital photographs (graded by independent investigators), and self-reported venous symptoms. Cross-sectional analysis at the baseline examination confirmed a high prevalence of any chronic venous disease (36.5%). Lower extremity oedema had the highest prevalence (30%) and ulceration the lowest prevalence. Women had a higher burden of chronic venous disease compared with men, with disease shifting toward greater severity with advancing age. In addition to the previously reported association of obesity, hypertension, and smoking with chronic venous disease,6 the current study reports higher rates of estimated cardiovascular risk based on the Framingham Risk Score with increasing severity of chronic venous disease. Further, participants with chronic venous disease had an existing burden of cardiovascular diseases including prior venous thrombo-embolism, a known inducer of chronic venous disease, but also peripheral artery disease. Patients with established heart failure in the MyoVasc cohort had a high prevalence of advanced chronic venous disease (C4–C6) of 14%.
Evaluation of 6-year follow-up data demonstrated that chronic venous disease predicts all-cause mortality in models adjusting for cardiovascular risk factors, and persisted in analyses excluding participants with prevalent cardiovascular disease at baseline. The predictive value of chronic venous disease was also demonstrated in the MyoVasc cohort of patients with established heart failure. While not the first study to connect venous disease to cardiovascular events,7 the current study adds comprehensive assessment of the spectrum of chronic venous disease, indicating that advancing severity by CEAP class portends higher risk of mortality. One interpretation of the elevated mortality risk with chronic venous disease includes the impact of shared risk factors that adversely influence the heart and drive venous hypertension. Given that leg oedema was the most common manifestation of chronic venous disease, it is also possible that the heightened risk reflects leg oedema as an initial sign of undetected heart failure.8 , 9 This possibility is supported by the stronger association of venous insufficiency with oedema and skin changes with prevalent cardiovascular disease and mortality risk compared with varicose veins. Still, the study findings indicate that a simple physical examination to identify chronic venous disease has potential clinical value in adults with or without established cardiovascular disease.
Though the present study did not directly evaluate the links between venous and arterial diseases, there is growing evidence for the concept of shared pathophysiology (Graphical Abstract). The vascular endothelium regulates both arterial and venous homeostasis, and cardiovascular risk factors lead to systemic endothelial dysfunction. Venous endothelial cells display reduced nitric oxide signalling in patients with diabetes, obesity, and smoking.10 , 11 Veins harvested from patients with chronic venous disease show higher oxidative stress, increased inflammation, and altered endothelial function.12 Biomarkers of thrombosis and inflammation are also higher in lower extremity samples from patients with chronic venous disease, suggesting common drivers of venous and arterial injury.13 Recent genetic studies of varicose veins have identified vascular development pathways that overlap with the genetics of venous thrombosis.6 The genetic epidemiology of venous thrombosis demonstrates extensive intersections with arterial disease, including lipids and plasminogen activator inhibitor type 1 (PAI-1).14 It will be important to evaluate whether the genetics of the spectrum of chronic venous disease identify shared pathways with heart failure or arterial diseases.
The findings generate many questions that will warrant investigation in future studies. The current study did not include functional venous evaluation including venous hypertension and venous reflux that would help elucidate the aetiology of venous symptoms. The follow-up study only evaluated for all-cause mortality without identification of specific types of cardiovascular events. It remains likely that chronic venous disease has differential associations with atherosclerotic, thrombotic, and heart failure events. The excess burden of chronic venous disease in women warrants additional evaluation to determine whether there are sex differences in the associations between venous and arterial diseases.15
The American Heart Association ran a public awareness campaign to ‘Take Your Socks Off’ at the doctors to identify the presence of peripheral artery disease. The study by Prochaska et al. supplies another reason to examine our patients’ legs for signs of chronic venous disease as a window to the heart. In patients without established cardiovascular disease and those with heart failure, observation for the presence of varicose veins, oedema, skin changes, and ulcers provides a simple clinical marker for excess risk. I will still explain to my patients with chronic venous disease that varicose veins are not the same as blocked arteries. But, I will be sure to comprehensively evaluate for the presence of cardiovascular risk factors, encourage exercise and risk factor modification, and await future research to identify the impact of venous targeted therapies on cardiovascular disease.
Funding
Dr. Hamburg is supported by grants from the American Heart Association 20SFRN35120118 and 20YVNR35500014 and the National Institutes of Health U54HL120163.
Conflict of interest: none declared.
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