We performed a systematic search of PubMed databases to identify relevant studies published between 2010 and 2023. The search terms included combinations of keywords such as “cardiovascular health,” “Life’s Simple 7,” “CVH paradox,” “misclassification bias,” “cumulative exposure,” “subclinical vascular disease,” “metabolic biomarkers,” “polygenic risk scores,” “epigenetics,” and “exposome.”

We included peer-reviewed articles, review papers, and meta-analyses that:

1. Discussed related concepts.

Studies were excluded if they:

1. Were not published in English.

We extracted relevant data from the included studies, focusing on:

1. Definitions and descriptions of the CVH paradox.

We synthesized the extracted data to identify common themes, gaps in the literature, and potential pathways contributing to the CVH paradox. The findings were organized into thematic sections, including misclassification bias, cumulative exposure, and personalized prevention elements, to provide a comprehensive overview and propose future research directions.

The synthesized data were reviewed and analyzed to highlight the implications for clinical practice and public health. We proposed a conceptual framework integrating traditional risk factors with novel personalized prevention elements to address the CVH paradox and improve cardiovascular outcomes. The review findings were discussed in the context of current prevention strategies, with recommendations for future research and practical applications.

Although associations between established risk factors and CVD morbidity and mortality have been reported extensively, understanding how other factors may affect a person’s CVH can help provide a more individualized approach to disease prevention and treatment. However, providing advice that is tailored to each individual based on their environmental, social, and genetic background may be challenging, especially if those individuals are considered to be in an overall healthy state. Identifying environmental exposures and novel disease mechanisms, such as epigenetic modifications, can help discover a set of therapeutic targets useful for directed screening and ultimately achieving better treatment for every individual.

The aim of this study is to provide a review of the determinants of individual cardiovascular risk that could explain the presently described cardiovascular health paradox.

A possible explanation for the residual risk is the misclassification bias for self-reported lifestyle factors (i.e., smoking, physical activity, and diet). People tend to over-report healthy habits, and therefore, present with a high CVH score [13, 14]. However, some of these individuals are in fact likely to have poor CVH and at risk of CVD, and some individuals sharing the same CVH score may be differently impacted in regard of likelihood incidence of cardiovascular events. Moreover, non-modifiable risk factors such as age, sex and family history are not comprehensively incorporated in the CVH score but play an important role in CVD risk. Age being the most important predictor of CVD risk, the relative added predictive value of the 7 CVH modifiable factors may be hindered at older ages. Although these explanations can partially justify the discrepancy between CVH score and CVD risk, an array of other biological explanations should be explored [15].

Another critical trope that should be addressed within the paradox is the notion of cumulative time-varying exposure to risk factors, and its impact on cardiovascular health. Fixed risk factors can not explain the health paradox. If fixed risk factors are not enough to explain the health paradox observed in cardiovascular prevention strategies, then surely other dimensions, particularly those that are not binary, need to be studied further.

One of these dimensions is cumulative exposure. To this day, our knowledge of cardiovascular risk factors worldwide (smoking, physical activity, patient and family history, dyslipidemia, elevated blood pressure, diabetes, obesity, sex and age), fails to address the impact of cumulative exposure in cardiovascular risk factors. For example, cholesterol is a known risk factor for cardiovascular events. Recent studies are increasingly showing [16] that independently of midlife LDL-C levels, the cumulative presence of LDL-C and during young adulthood is a risk factor in and of itself [17]. This is especially true in patients with familial hypercholesterolemia [17], where the cumulative factor of LDL-C presence has been proven to be independently strongly associated with the occurrence of major cardiovascular events. Therefore, Ference et al. suggested that monitoring of atherosclerotic plaque burden progression may be relevant to assess clinical benefit of primordial prevention, and provide individuals evidence of benefits from maintaining optimal lipid levels [18].

Similarly, cumulative time-varying exposure to elevated blood pressure has also been shown to increase the risk of CVD regardless of fixed measurements [19]. This again suggests that our classification of cardiovascular risk considers the lifetime-evolution of blood pressure for each individual so as to better anticipate their risk of developing CVD [20].

Therefore, documenting a reduced rate of atherosclerotic plaque burden progression, rather than a reduced incidence of clinical cardiovascular events, may be a more intuitive and accurate metric for assessing the clinical benefit of primordial and primary prevention. Using this metric, nearly every person can assess how much he or she is benefiting from maintaining optimal lipid levels. C-reactive protein has also become a topic of interest as cumulative time exposure: new studies are proving that high sensitivity CRP is associated in a dose-response pattern to increased cardiovascular risk and myocardial infarction, depending on the number of years exposed to elevated levels of CRP-mediated inflammation [21].

Another promising lead to explain the health paradox in relation to cumulative exposure, is to evaluate the accumulation of multiple risk factors over time, rather than one element only. This is particularly true for risk factors that are composite. Cumulative social risk, for instance, is in part a consequence of environmental pollutants, cumulative exposure to bad air quality and PM_2.5 pollutants in addition to socio-demographic risk factors. These are now being shown to increase overall social risk for CVD and mortality [22]. Increasing numbers of social risk factors is proportionally linked to the unlikeliness of ideal cardiovascular health [23].

Another example is impaired fasting glucose, a type of pre-diabetes, impaired fasting glucose is largely mediated by the combined presence of dyslipidemia and hypertension; and this combined presence has manifested itself to be independently associated with CVD risk [24]. The fact that two independent risk factors can create a third is a pattern that deserves to be studied further so that guidelines for prevention can adapt to the notion of cumulative exposure and its associated cumulative risk.

Furthermore, this pattern has exhibited molecular sense. Epigenetic modules could indeed be implicated [25] as a response to the cumulative exposure to traditional cardiovascular health determinants. This would help explain the physiopathology behind the theory of cumulative exposure.

Overall, the impact of risk accumulation over time is a notion that already has been used in practice before. Smoking, for instance, is evaluated in number of pack-years smoked rather than in binary features. The case of smoking has proved many times that cessation is not enough to annihilate the added cardiovascular risk completely [26]. Extrapolating to the theory of cumulative exposure, this suggests it could be promising to evaluate not only the impact of accumulation on risk levels, but also on the effectiveness of cessation. Furthermore, the study of cumulative risk is promising in terms of discovering new risk factors outside of traditional health determinants. Some factors may only have an impact when accumulated over time. This is already the case with reproductive risk factors, such as postmenopausal status in women, for example, which have been shown to decrease the likeliness to reach ideal cardiovascular health [27].

Overall, studying cumulative exposure is promising in the impact it could have on the discovery of factors that have so far been studied solely in a fixed, and not cumulative, manner in regards to cardiovascular health, hence furthering our understanding of the cardiovascular paradox.

Misclassification bias in self-reported lifestyle factors is a significant challenge in CVH assessment. Individuals often over-report healthy behaviors, leading to inflated LS7 scores and misrepresentation of true cardiovascular risk. Objective measures, such as biochemical verification of smoking status and wearable devices for physical activity tracking, could reduce this bias. Implementing these measures in routine clinical practice and large epidemiological studies would enhance the accuracy of CVH assessments and help mitigate the paradox.

Our findings suggest that cumulative exposure to risk factors over time is a more accurate predictor of CVD than single-point assessments. For instance, long-term exposure to elevated LDL cholesterol and blood pressure has a stronger association with cardiovascular events. This insight emphasizes the need for longitudinal monitoring and a life course approach to CVH assessment. Healthcare providers should consider cumulative risk in their prevention strategies, focusing on sustained lifestyle interventions and regular monitoring of risk factors.

Incorporating personalized prevention elements offers promising avenues to address the CVH paradox:

1. Markers of Subclinical Vascular Disease: Early detection of subclinical vascular changes, such as arterial stiffness and endothelial dysfunction, can identify individuals at high risk for CVD before clinical symptoms appear. Routine screening using these markers could improve early intervention strategies and prevent disease progression.

The integration of personalized prevention elements into CVH assessments has significant implications for clinical practice and public health. Personalized approaches can lead to more accurate risk predictions, enabling tailored interventions that address individual risk profiles. This shift towards precision medicine in CVD prevention can improve patient outcomes and reduce healthcare costs by preventing disease progression and complications.

Future research should focus on developing and validating comprehensive risk models that incorporate traditional risk factors, subclinical markers, metabolic biomarkers, genetic information, and environmental exposures. Large-scale studies and clinical trials are needed to establish the effectiveness of these personalized prevention strategies in diverse populations.

Future studies are needed to gain more insight into the CVH paradox by: 1) describing the prevalence of the CVH paradox; and 2) investigating the mechanisms underlying the CVH paradox by evaluating a panel of potential causes across various geographical settings.

The achievement of these goals would require optimal identification of high CVD risk patients, at early stages of life and as precisely as possible (notion of “full health maintenance from before birth to golden years”). Therefore, it is crucial to combine the traditional risk factors with subclinical and circulating intermediary biomarkers, genetics, epigenetics and more broadly the exposome of each individual.

The growing accessibility of detailed information such as polygenic risk scores holds the promise to shift the perspective of CVD prevention towards a more individualized practice, although more progress needs to be made to render affordable and accessible mass assessment of other emerging markers. It is of primary importance for public health that the CVH paradox be better understood and addressed in order to reduce CVD morbidity and mortality. Prevention specialists have recognized the importance of applying a more individualized preventive care, yet, it remains to be acted upon and given more awareness for concrete implementation [75]. In order for personalized prevention to succeed, it is necessary to understand the mechanisms behind the approach and to ensure effective communication is being upheld between researchers, physicians, and patients. Widespread adoption of personalized prevention is a major untaking that requires both an international and a multidisciplinary effort. Specifically, personalized prevention is a public health priority, that would require involvement and support from politicians, public health officials, non-governmental organizations, scientists, epidemiologists, clinicians, and community members and stakeholders. Although it may be difficult and costly to carry out such a precise method of prevention in the short-term, implementation strategies should be uncomplicated, inexpensive with a long-term perspective to maximize sustainability impact that includes lowering the overall healthcare and economic burden that is associated with CVD.