Unveiling HPV's hidden link: Cardiovascular diseases and the viral intrigue

Abstract

Cardiovascular diseases (CVD) remain a major global health challenge, with an escalating impact on mortality despite advancements in managing conventional risk factors. This review investigates the intricate relationship between human papillomavirus (HPV) and CVD, shedding light on a novel aspect of cardiovascular health. Despite significant progress in understanding and managing traditional CVD risk factors, a substantial proportion of CVD cases lack these conventional markers. Recent research has unveiled HPV, a prevalent sexually transmitted infection, as a potential unconventional risk factor for CVD.

This review delves into the underlying mechanisms linking HPV to CVD pathogenesis. HPV's influence on vascular endothelium and induction of systemic inflammation are key contributors. Additionally, HPV disrupts host lipid metabolism, further exacerbating the development of atherosclerosis. The link between HPV and CAD is not merely correlative; it encompasses a complex interplay of virological, immunological, and metabolic factors. Understanding the connection between HPV and CVD holds transformative potential. Insights from this review not only underscore the significance of considering HPV as a crucial risk factor but also advocate for targeted HPV screening and vaccination strategies to mitigate CVD risks. This multidisciplinary exploration bridges the gap between infectious diseases and cardiovascular health, emphasizing the need for a comprehensive approach to combating the global burden of cardiovascular disease. Further research and clinical guidelines in this realm are essential to harness the full scope of preventive and therapeutic interventions, ultimately shaping a healthier cardiovascular landscape.

1. Introduction

Cardiovascular diseases (CVD) remains the primary worldwide cause of mortality, causing over 17.3 million deaths annually, a figure anticipated to rise to 23.6 million by 2030.^1,2 Even with significant advancements in efforts to minimize conventional risk factors like smoking, dyslipidemia, high blood pressure, and diabetes, cardiovascular disease remains the foremost cause of both mortality and disability worldwide.^2,3 While the significance of traditional risk factors is widely recognized, they do not provide a comprehensive explanation for individuals affected by cardiovascular disease alone.²

Certainly, approximately 20% of individuals afflicted with cardiovascular diseases lack any of these traditional risk factors.⁴ Recognizing the modifiable unconventional risk factors for cardiovascular diseases is essential in formulating effective treatment and prevention methods to decrease CVD occurrences.

2. Global incidence OF HPV

Infections with several viruses like HIV, Epstein–Barr virus, and cytomegalovirus have been proposed as potential risk factors for CAD likely due to their role in promoting a persistent inflammatory state.^5,6 In this context, HPV, consisting of over 200 types, among which at least 12 are oncogenic types, is the most widespread viral infection transmitted through sexual contact that affects a majority of sexually active individuals, encompassing both men and women on a global scale.⁷ Nearly every individual experience a genital HPV infection at least once in their lifetime⁸ with approximately 1 out of 3 men aged 15 and above carry at least one strain of human papillomavirus (HPV), and 1 in 5 are infected with one or more of the high-risk HPV types. These figures reveal that men commonly carry genital HPV infections, underscoring the significance of including men in initiatives aimed at managing HPV infections and decreasing the occurrence of HPV-related diseases in both men and women.⁹ While most HPV infections don't show symptoms, they can result in enduring complications and even death.⁹ Various techniques for HPV detection have proven their efficacy in specific conditions associated with male HPV. Nevertheless, none of these methods has been approved for application in men. The FDA has not approved any HPV test for men, and no test has been authorized for detecting the virus in areas other than the cervix.¹⁰

HPV frequently leads to the formation of benign lesions that develop on the hands and soles or mucous membrane growths called warts, which can serve as a sign of HPV presence in an individual.¹¹ Various skin clinical presentations are:

• 1.Genital warts manifest as flat lesions, small bumps resembling cauliflower, or tiny stem-like protrusions. In women, they primarily occur on the vulva but can also develop near the anus, cervix, or inside the vagina. In men, genital warts appear on the penis, scrotum, or around the anus. Typically, genital warts do not cause discomfort or pain, although they might itch or feel tender.
• 2.Common warts are characterized by rough, raised bumps and typically appear on the hands and fingers. While often just unsightly, they can also cause pain, be prone to injury, or bleed in some instances.
• 3.Plantar warts are firm, grainy growths that commonly develop on the heels or balls of the feet, often causing discomfort.
• 4.Flat warts are characterized by their flat-topped, slightly raised appearance. They can emerge on various parts of the body, but children often develop them on the face, while men tend to get them in the beard area, and women typically on their legs.^12,13 Globally, the combined prevalence rate was 31% for all types of HPV and 21% for high-risk HPV. HPV-16 emerged as the most common HPV genotype, accounting for 5%, followed by HPV-6 at 4%. The prevalence of HPV was higher among adolescents, reaching its peak between the ages of 25 and 29, and then either remaining stable or exhibiting a slight decline afterward.^14,15

2.1. HPV screening and CVD risk - an unsolved concern

HPV vaccines, such as Gardasil and Cervarix, have been shown to be extremely successful in preventing infection with the targeted HPV subtypes.¹⁶ However, they do not provide protection against all HPV subtypes, which means that some individuals may still be at risk of HPV infection. The available HPV vaccines target specific high-risk subtypes, such as HPV-16 and HPV-18, which are responsible for a significant proportion of HPV-related cancers.¹⁷ It's important to base healthcare decisions and screening practices on established guidelines and evidence. Currently, HPV screening is recommended for the prevention and early detection of HPV-related cancers, especially for cervical cancer in women. According to WHO, screening should start in women from the age of 30, with a validated HPV test every 5–10 years. Over 47 million women were vaccinated against HPV (full course) through immunization programs by 2015, worldwide.¹⁸ However, it's not a standard practice for assessing or managing cardiovascular risk. HPV patients should undergo a thorough evaluation of traditional cardiovascular risk factors, which include: blood pressure measurement, cholesterol level testing, blood sugar assessment (especially for those at risk of diabetes), family history of CVD, smoking status and lifestyle factors, such as diet, exercise, and alcohol consumption¹⁹ (Table 1).

Table 1.

Summarizing various lifestyle factors and disease conditions that have an effect in higher risk of HPV infection and CAD.

Lifestyle Risk factors/Disease conditions	Association with HPV	Association with CAD
Age	Between 25 and 29 years are at a higher risk43	20 years and older but less than 65 years are at a higher risk44
Smoking	Promotes HPV E6 and E7 expression45	Associated (CDC Fact sheet)
Excessive Alcohol Consumption	Associated46	Associated47
Obesity	Associated48	Associated49
Hypertension	Associated50	Associated51
T2DM	Associated52	Associated53
Dyslipidemia	Associated (Association of Dyslipidemia)	Associated54
Immunocompromised/Inflammatory conditions	High risk in autoimmune disorders especially RA and SLE55,56	High risk in immunocompromised as well as in specific autoimmune disorders (RA and SLE) (35175848)
Sleep apnea	Associated57	Associated58
Kidney function	Increased serum urea, creatinine, and uric acid levels and developing ESRD. Association of Dyslipidemia, Renal dysfunction, and Uricemia with HPV mediated Cervical Cancer	Chronic kidney disease as well as high blood urea nitrogen and high serum creatinine59

3. HPV and cardiovascular disease - a growing correlation

An interesting study mentioned that 40.8% women tested positive for HPV DNA, 3.0% had cardiovascular diseases, and 9.0% had received the HPV vaccine. The study found a connection between vaginal HPV infection and cardiovascular diseases (odds ratio [OR] = 1.66, 95% confidence interval [CI] 1.28–2.16). This association remained significant (OR = 1.54, 95% CI 1.15–2.08) even after adjusting for sociodemographic factors, lifestyle behaviors, medical history, family history of cardiovascular diseases, and the use of antihypertensive drugs. There was no significant association found among individuals who were vaccinated against HPV (OR = 0.50, 95% CI 0.07–3.51), whereas it was present in those who were not vaccinated (OR = 1.63, 95% CI 1.18–2.25). This data clearly indicates the relationship between HPV infection and cardiovascular diseases. There was no significant association observed in women who had received the HPV vaccine. Though the effect of HPV vaccination on cardiovascular diseases requires further investigation²⁰ (Table 2).

Table 2.

Summarizing targeted therapies for HPV specifically aimed at reducing cardiac diseases.

Therapy	Mechanism of Action	Potential Impact on Cardiac Diseases
Antiviral Agents	Inhibit HPV replication and spread60	Potential reduction in HPV-related inflammation, possibly reducing cardiac complications associated with HPV.
Immunotherapy	Boost the immune response against HPV.61	Strengthened immune defense might limit HPV-related cardiac inflammation.
Vaccination	Preventive measure against HPV infection.62	Reduction in HPV incidence could lower the risk of subsequent cardiac diseases related to persistent HPV.
Anti-inflammatory Agents	Target inflammation caused by HPV infection63	Reduction in systemic inflammation, potentially benefiting cardiac health.
Antioxidants	Combat oxidative stress linked to HPV64	Minimization of oxidative damage, potentially reducing cardiac complications associated with HPV-induced inflammation.
Regular Screening And Management	Early detection of HPV and related complications.	Prompt intervention and management could prevent or mitigate cardiac issues.
Lifestyle Modifications	Healthy diet, exercise, and stress management.	Strengthen overall immune response, potentially reducing HPV-related cardiac complications.

HPV is recognized as a pathogen that predominantly targets epithelial tissues. Studies found HPV 16 can also be found in the vascular endothelium²¹ and endothelial cells (ECs) make up the inner lining of both blood and lymphatic vessels. Viral HPV oncoprotein E5 increased Vascular Endothelial Growth Factor (VEGF) expression. The introduction of an epidermal growth factor receptor (EGFR) inhibitor markedly inhibited VEGF expression, indicating that E5 triggers VEGF expression by activating EGFR. This activation of EGFR by E5 was concurrent with the phosphorylation of Akt and ERK1/2, which are also implicated in VEGF expression. Moreover, the mRNA stability of VEGF remained unaffected by E5. However, in E5-expressing cells, the activity of the VEGF promoter could be influenced by inhibitors targeting the EGFR, MEK-ERK1/2, and PI3K/Akt pathways. These new findings collectively indicate that HPV 16 E5 enhances VEGF expression by activating EGFR, MEK/ERK1/2, and PI3K/Akt.²² HPV affected vascular endothelium is thus one of the precursors of atherosclerotic plaque formation. On the other hand HPV, while limited to mucosal lesions, could contribute to coronary artery disease by fostering a systemic inflammatory condition.²³ The intriguing relationship between inflammation and HPV-induced lesions was first observed by Mazibranda et al in samples obtained from patients with normal cervical cytology, cervical intraepithelial neoplasia (CIN), and invasive cervical cancer (ICC).²⁴ Interestingly the Toll-Like Receptor Signaling Pathways significantly contribute to atherosclerotic inflammation by triggering the synthesis of cytokines, adhesion molecules, and reactive nitrogen and oxygen species.²⁵ Studies have shown that different high-risk HPV types can modulate TLR expression, interfering with TLR signaling pathways and potentially leading to persistent viral infection.²⁶ Furthermore Notch1 overexpression has been associated with HPV-infected cell lines, inhibiting p53 apoptosis through the P13K-protein kinase B/AKT pathway, resulting in p53 degradation²⁷ accelerating the process of atherosclerosis by inducing inflammation.²⁸ Also, the AIM2 inflammasome responds to dsDNA released from infected HPV cells, leading to the secretion of effector cytokines IL-1β, IL-18, and IFN-β, which drive the progression of the inflammatory process in atherosclerosis.²⁹ Research has indicated that tumors associated with HPV demonstrate notably elevated expression levels of COX1 and COX2 in both neoplastic epithelial cells and vascular endothelial cells, suggesting their role in the pathogenesis of the disease.^30,31 Additionally, HPV16 oncoproteins have been associated with increased COX-2 expression, further linking HPV oncogenes to potent inflammatory cascades. Continual HR-HPV infection results in the integration of viral DNA into the host cell genome, the heightened expression of viral oncogenes (E5, E6, and E7), and subsequent inflammation by upregulating COX2 expression, thus intensifying the progression of atherosclerosis. HPV E6 and E7 oncoproteins have also been found to dysregulate cellular processes involved in the activation of the canonical WNT pathway.^32,33 Studies have shown that HPV16 and HPV18 E6 oncoproteins, as well as HPV11 E6 oncoproteins, induce the nuclear localization of Caspase-8, leading to apoptosis and activated apoptosis causing coronary atherosclerosis.^34,35 Additionally, HPV16 has been associated with changes in the lipid composition of cell membranes, leading to increased levels of free cholesterol extracted from the plasma membrane.³⁶ Moreover, by disrupting host metabolism, especially lipid metabolism, HPV may contribute to this process.³⁷ Studies have shown an association between cervical cancer and a disordered lipid profile, with elevated total cholesterol, triglycerides, and LDL and low HDL levels.³⁸ Since HPV is the predominant cause of cervical cancer, it suggests that HPV may also be associated with dyslipidemia. HPV oncoprotein E6 has been shown to increase lipid metabolism partially through p53 degradation, which can increase triglyceride levels and contribute to CAD.^39,40

A research study utilizing NHANES (National Health and Nutrition Examination Survey) data from 2003 to 2006 revealed a connection between HPV, particularly oncogenic strains, and a higher occurrence of self-reported diagnoses of myocardial infarction and stroke among women residing in the United States.⁴¹ The research conducted by Kuo et al put forward the hypothesis that HPV infections might play a role in the development of CVD. This hypothesis is based on the observation that viral oncoproteins interact with the cellular tumor-suppressor protein p53 and trigger its degradation, which could be linked to atherosclerosis.⁴²

Another interesting study by researchers in South Korea have established a link between infection with high-risk strains of human papillomavirus (HPV) and a heightened risk of CVD. The study encompassed 63,411 Korean women aged 30 and above, all free of cardiovascular disease at the start, who were monitored from 2011 to 2016. The individuals in the study had a median age of 40 and a median body mass index (BMI) of 22. After adjusting for BMI and other cardiovascular risk factors like smoking, alcohol consumption, and physical activity, researchers discovered that women with high-risk HPV were 22% more likely to develop cardiovascular disease. Over the course of 261,598.9 person-years of follow-up, 1122 new cases of cardiovascular disease (CVD) were detected, corresponding to an incidence rate of 4.3 per 103 person-years. High-risk HPV infection was notably linked to the occurrence of new-onset CVD.¹⁹

A cross-sectional study was carried out using data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2003 to 2016 which involved 9353 women aged between 20 and 59 years old who were screened for vaginal HPV DNA. Among these women, 40.8% tested positive for HPV DNA, out of which 3.0% had cardiovascular diseases. Additionally, 9.0% of the women had received the HPV vaccine. The study found a correlation between vaginal HPV infection and cardiovascular diseases (odds ratio [OR] = 1.66, 95% confidence interval [CI] 1.28–2.16). This association remained statistically significant (OR = 1.54, 95% CI 1.15–2.08) even after adjusting for sociodemographic characteristics, lifestyle behaviors, medical history, family history of cardiovascular diseases, and the use of antihypertensive drugs. There was no significant association observed among individuals who were vaccinated against HPV (OR = 0.50, 95% CI 0.07–3.51), whereas it was present in those who were not vaccinated (OR = 1.63, 95% CI 1.18–2.25). This study concludes a established link between HPV infection and cardiovascular diseases. However, this association was not statistically significant among women who had been vaccinated against HPV.²⁰

4. Conclusion

The purpose of this review is to consolidate recent findings on the association between HPV and CVD, providing valuable insights into potential preventive strategies and therapeutic interventions. Certainly, a more in-depth analysis of the limitations and gaps in the existing literature regarding coronary artery disease (CAD) and human papillomavirus (HPV) would be beneficial and further research is imperative to elucidate the precise mechanisms and establish guidelines for HPV screening and vaccination in the context of cardiovascular health. Limited clinical studies with small sample sizes hinder our understanding of the HPV-CAD relationship. Causality is challenging to establish, as while an association is observed, a direct link remains uncertain. HPV's strain heterogeneity and its specific role in cardiovascular health require further exploration. Mechanistic insights into how HPV contributes to CAD are lacking, hindering the development of targeted therapies. Long-term studies are needed to assess the persistence of HPV infection's impact on CAD development. Confounding factors like smoking and obesity must be addressed for accurate conclusions. Ethno-geographic variations and the role of immune responses in HPV-related cardiovascular inflammation need further investigation for a comprehensive understanding. Addressing these limitations and filling these gaps in the literature is crucial for gaining a more comprehensive understanding of the relationship between HPV and CAD, potentially leading to more effective prevention and treatment strategies. Future research efforts should focus on these aspects to advance our knowledge in this field.

Funding

None.