Introduction

Since the 1970s, there has been a 67 % decrease in the incidence of cardiovascular deaths per 100,000 in the US population, with much of the improvement attributed to primary and secondary prevention strategies that include statin therapy as a key component [3]. From 2000 to 2006, life expectancy in the USA has increased by 1.2 % when measured from birth, and 5.1 % when measured from the age of 65 years. This improvement in mortality was largely driven by a 33 % decrease in age-adjusted death from coronary heart disease (CHD) [4]. These positive trends are related to significant decreases in total cholesterol, systolic blood pressure, and smoking, as well as continued improvements in secondary prevention therapies [4]. Despite these remarkable achievements, cardiovascular disease still remains the leading cause of mortality for adults in the United States [5]. In fact, it has been proposed that by 2030, without any significant change in prevention or treatment strategies, the number of adults with heart disease will increase from 36.9 to 40.5 %, or 116 million American adults [6]. This raises the question, where do we go from here if our goal is to remove cardiovascular disease (CVD) as the number-one cause of mortality in the USA?

In order to address this question we need to understand exactly where we stand as a society with CVD risk factors. Despite the noted progress in several of the aforementioned key risk factors for CVD, there is still room for improvement. For example, the 2011 data from the Centers for Disease Control and Prevention indicated that 21.6 % of men and 16.5 % of women, totaling 43.8 million US adults, continue to smoke [7]. Hypertension among adults in the USA remains at 28.6 %, with only 53.3 % having their blood pressure controlled [8]. The percentage of American adults with high LDL-C has remained around 34 % over the past decade, totaling 71 million, with less than half being treated, and of that subgroup, only 1 out of 3 brought under control [9]. It could be argued that if we had the ability to achieve our stated goals with all these risk factors, the benefits accrued would remove CVD as the leading cause of mortality.

However, these improvements in cardiovascular disease prevention and treatment have been tempered by increasing rates of obesity and diabetes [4]. The overweight and obesity epidemic now includes almost 70 % of the adult US population, and within that ever increasing number the prevalence of visceral obesity has likewise risen to 53 % [6]. In concert with the obesity epidemic, the combined incidence of pre-diabetes and diabetes has risen to almost 50 % of the adult population (13 % diabetes and 36 % pre-diabetes), and possibly even more troubling is that the incidence has doubled in children, where 34 % are currently overweight or obese [6]. This manuscript will focus on the role of statin therapy in these negative epidemiologic trends over the past quarter century, specifically regarding obesity, the metabolic syndrome, and their association with subclinical inflammation and climate change.

Obesity and the metabolic risk factors

Statins are effective for secondary prevention, however, there remains controversy as to their effectiveness in certain subgroups in primary prevention [10-12]. Only 60–80 % of obese subjects appear to be at increased risk for CVD, such that obese subjects with normal metabolic status may not have an increased CV risk when compared to obese or even normal weight subjects with metabolic syndrome [13-15]. A potential explanation for this phenomena is the site where fat is stored. For example, if the fat stores are predominately in the periphery and subcutaneous tissues, there are frequently no associated metabolic abnormalities and no resultant increased CV risk. However, if the fat is stored centrally or with a visceral distribution, the likelihood of associated metabolic abnormalities markedly increases, resulting in a greater CV risk [16]. Therefore, in those obese subjects with metabolic syndrome, the risk of a CV event doubles [17]. In the National Health and Nutrition Examination Survey III (NHANES III) cohort of adults > 50 years, 87 % of type-2 diabetics had metabolic syndrome, accounting for much of the CHD equivalency status attributed to those with diabetes. Further support for the idea that metabolic syndrome drives up the CV risk in diabetics was demonstrated by the fact that 13 % of the NHANES cohort subjects who were diabetic but without metabolic syndrome had a similar incidence of CHD as those with neither diabetes nor metabolic syndrome [18].

In the Women’s Health Across the Nation (SWAN) study, metabolically normal (defined as two or less risk factors for metabolic syndrome), overweight or obese women were evaluated for subclinical evidence of atherosclerosis via carotid intimal media thickness (CIMT), coronary or aortic artery calcification (CAC), or aortic pulse wave velocity [19]. In the SWAN study, there was a continuum in the spectrum of subclinical CVD: from patients with normal weight, to overweight/obese patients who were metabolically benign, to finally those overweight/obese patients with metabolic syndrome (Table 1). Those designated as metabolically benign had worse metabolic parameters, including higher CRP, than the control non-overweight, non-metabolic group. The mean BMI in the metabolically-benign, overweight/obese group was 30.8 kg/m2, and many exhibited one metabolic risk factor plus an elevated CRP, suggesting the presence of an early or quiescent form of metabolic syndrome. This represents a continuum of metabolic risk that had not yet manifested the obligatory three components necessary for the diagnosis of the syndrome, yet still exhibited subclinical atherosclerosis [19].

Table 1 SWAN Baseline Data
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In the Aerobics Center Longitudinal Study (ACLS), 42,265 subjects were followed from 1979 to 2003, with 13 % classified as obese using BMI > 30 kg/m2, and 29 % by using body fat percentage (> 25 % in men and > 30 % in women). Of those deemed obese, 46 % were considered metabolically healthy (1 or less metabolic risk factors). In those obese patients designated as metabolically healthy, over a 20-year follow-up they demonstrated a 38 % lower CV mortality than those obese patients who were diagnosed with metabolic syndrome. Subjects who were obese but metabolically normal had higher mortality than normal weight, metabolically normal subjects. However, when the metabolically normal obese subjects were adjusted for physical fitness, those achieving cardio-respiratory fitness > 9 METS mirrored the cardiovascular risk for normal weight, metabolically normal subjects [20••]. Therefore, improved cardio-respiratory fitness should be considered a characteristic of the subset for the metabolically healthy, obese phenotype Once fitness is accounted for, metabolically healthy but obese individuals appear to have a relatively benign condition, with a similar CVD prognosis as metabolically normal, normal weight individuals.

Obesity and subclinical inflammation

Obese patients with metabolic syndrome had significantly greater levels of small dense LDL particles and C-reactive protein (CRP) than obese patients without the syndrome [21]. In the SWAN trial, 35 % of the overweight or obese women without metabolic syndrome had a CRP > 3 mg/L and early evidence of subclinical atherosclerosis [19]. In a study by Miller et al., among the CV risk factors, obesity showed the greatest attributable risk for an CRP > 3 m/L [22] (Figure 1).

Fig. 1
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Weighted multiple logistic regression analysis showing attributable risk for CRP > 3 mg/L from CV risk factors

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Obesity, principally abdominal and visceral obesity, when associated with an adipokine-induced inflammatory background increases the risk of CV. Adipokines, such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP), among others, are elevated with excess adiposity, especially when the adiposity is associated with visceral rather than subcutaneous adipose tissue [23].

Therefore, the definition of obesity as a BMI > 30 kg/m2, which is the current standard to define weight status, may often be misleading when considering the risk for CVD. The converse may also be true in that central or visceral fat can lead to metabolic syndrome even when BMI levels <25 kg/m2, such that 20–40 % of “normal weight or mildly overweight” people may manifest metabolic syndrome and be at increased risk for CVD [13, 24].

Statins, obesity and metabolic risk factors

A 30-year NHANES trend indicated that in 1976, only 17 % of adults achieved an LDL < 100 mg/dl; this improved to 31 % in 2006. This same analysis also showed a slight improvement from 79 to 81 % in achieving an HDL-C > 40 mg/dl, but a slight worsening in achieving a triglyceride level < 200 mg/dl, from 84 to 82 % [25]. This data is not surprising given that statins, which are the most widely prescribed medications in the USA, are potent reducers of LDL-C, with far less effect on HDL-C and triglycerides.

The largest primary prevention trial on statins, JUPITER, enrolled 17,802 subjects without evidence of CVD but with a CRP ≥ 2 g/L and an LDL-C < 130 mg/dl. In JUPITER, even though diabetics were excluded, the mean BMI was 28.3 kg/m2 and 42 % of the subjects had metabolic syndrome. JUPITER demonstrated statin-induced reductions in combined CVD in those with and without metabolic syndrome, as well as those at every weight [26].

The Multi-Ethnic Study of Atherosclerosis (MESA) trial evaluated the associations between obesity, metabolic syndrome, CRP and subclinical atherosclerosis, measured by coronary artery calcium score (CAC) or carotid intima medial thickness (CIMT) [27]. In this analysis, both obesity and metabolic syndrome were strongly associated with subclinical atherosclerosis as measured by both parameters, independent of CRP. In the MESA subgroup of subjects who met the JUPITER eligibility criteria of a CRP ≥ 2 mg/L, there was no association with CAC and only a mild association with CIMT in the absence of obesity [27].

The JUPITER cohort was included with 25 other randomized statin trials, in the largest meta-analysis to date, the Cholesterol Treatment Trialists’ (CTT) Collaboration, that evaluated over 170,000 subjects and demonstrated that a 1-mmol/L (38.7 mg/dl) decrease in LDL-C reduced the combined CVD events (incidence) by 22 % [28]. The mean baseline LDL-C in CTT was (143 mg/dl) and averaged a reduction in LDL-C with statins of (41.3 mg/dl) to 102 mg/dl. The CTT meta-analysis evaluated a myriad of subgroups demonstrating a consistency in benefits, including those with or without diabetes, with or without metabolic syndrome, and in every weight category. In the CTT analysis, primary and secondary prevention trials were combined; however, a subsequent analysis focused on subjects at lower risk, whose 5-year risk was less than 10 % [29]. In the follow-up analysis, even those with a 5-year risk less than 5 % demonstrated that a 1-mmol/L reduction in LDL-C produced 11 fewer vascular events per 1,000 subjects treated over 5 years [29].

In a study of 10,043 dyslipidemic veterans followed for 10 years, the mortality rate was lower among those using statins than those who were not. However, when fitness level was included, the mortality rate further decreased as the fitness improved [30•]. For those who achieved > 9 METS on an exercise tolerance test, the hazard ratio was 0.30 (p <0.0001) compared to those who were least fit, achieving ≤ 5 METS. Thus, in this analysis, statins and fitness were independently associated with lower cardiovascular mortality [30•].

Exposure of obesity and metabolic syndrome to particulate matter air pollution

The World Health Organization (WHO) estimated that the small particulate matter PM2.5 (<2.5 ưm) in the atmosphere contributes to about 800,000 premature deaths annually, categorizing this as the 13th leading cause of death in the world [31]. An updated American Heart Association (AHA) scientific statement confirmed that exposure to elevated levels of PM2.5 over a few hours to weeks can trigger CV events, while longer exposure over several years can increase the CV risk to a far greater extent, leading to a 10–20 % increase in CV mortality per 10 μg/m3 in PM2.5 [32•]. Conversely, this analysis also determined that reductions in PM2.5 can have a beneficial effect, reducing CV mortality within a span of a few years. The Harvard Six Cities Study recently extended its follow-up from 1974 to 2009, and disclosed that even with an average PM2.5 of <18 μg/m3, a 10-μg/m3 increase was associated with a 14 % increase in all-cause mortality and a 26 % increase in CV and lung cancer mortality. The relationship between PM and CV mortality was linear down to a PM2.5 of 8 μg/m3, a level below the national average of 12 μg/m3, thus placing over 100 million US citizens in areas of unhealthy exposure to PM [33].

A 4.2-μg/m3 increase in PM2.5 over a year was noted to be equivalent to 3–4 years of vascular aging and increased carotid intima media thickness (CIMT) [34]. This difference in PM is equivalent to annual exposure differences between living in Fairfield, Connecticut (12.8 μg/m3), or Baltimore, Maryland (17 μg/m3) [35].

Visceral adipose in the absence of subcutaneous adipose can predispose to insulin resistance, inflammation and increased CV risk [36]. Although the site of fat storage appears to indicate how a given individual will manifest their CV risk, this may not always the case [37]. The complex nature of these concepts suggest that obesity, per se, may not always explain a causal relationship to increased CV risk. The association between PM-induced higher CRP levels is stronger in children than in adults [38]. The stronger association in children may be due to children spending more time outside exposed to environmental PM and/or the adult population’s confounding issues, such as the far greater use of anti-inflammatory medications, including statins, which have been shown to lower inflammation [39].

The inflammatory process, whether associated with overt obesity or hidden as visceral fat, may be influenced by adverse environmental conditions such as PM2.5 in the atmosphere [40••]. Several trials have suggested that obese and/or diabetic subjects are more vulnerable to the acute effects of PM on BP and vasculature [41, 42]. In the Women’s Health Initiative and Veteran’s Normative Aging studies, the association between increased inflammatory markers, CV events, and PM2.5 increased with higher BMI, as well as with increased waist-to-hip ratios [43, 44]. Although the MESA trial did not confirm a clear difference in subclinical atherosclerosis with BMI, there does appear to be a plausible mechanism for such a relationship [45]. PM2.5 particles are inhaled deeply into the lungs, depositing in alveoli and then entering the pulmonary circulation, inducing a systemic inflammatory response [36, 39, 45]. Obese subjects tend to have a higher PM2.5 dose–response relationship, due to increased tidal volume and resting minute ventilation as a consequence of their obesity [46]. Exposure to PM2.5 may impact atherosclerosis in a manner similar to other risk factors, such as diabetes, lipids, smoking, etc., stimulating an immune response with macrophages, increased expression of inflammatory mediators, and smooth muscle proliferation [32•, 40••].

In an experimental model, obese rats were exposed to near-ambient levels of nitrogen dioxide, which was found to significantly raise triglyceride levels and lower HDL-C, however, no such effect was noted with identical treatment in non-obese rats [42]. An increase in inflammatory cytokines as a result of dietary intake may occur in the absence of weight gain or obesity and may be part of a broader inflammatory response, secondary to external factors such as air pollution [40••, 41, 47]. Thus, air pollution, when superimposed with increased visceral fat with or without overt obesity, may induce an increased inflammatory response (metaflammation), which predisposes the individual to increased CV risk [39] (Figure 2).

Fig. 2
figure 2

Relationships between air pollution, obesity and CV risk

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How can statin therapy fit into the equation of metaflammation-induced CVD?

Trial data supports the notion of statin therapy benefitting those with obesity, metabolic syndrome, and subclinical inflammation in both primary and secondary prevention [28]. Although no trial, per se, has evaluated the impact of statin therapy on subclinical inflammation induced from air pollution, meta-analyses have demonstrated the effectiveness of statins over a wide geographic distribution that included many subjects living in areas known to have higher PM levels [28].

As noted previously, in the JUPITER trial, rosuvastatin reduced CVD in those with metabolic syndrome; however, they also had to have a CRP ≥ 2 mg/L. Post-hoc analyses of AFCAPS/TexCAPS and ASCOT hypothesized that CV benefits were also noted in those with metabolic syndrome and/or multiple CHD risk factors but whose CRP <2/L [48-50]. Statins have demonstrated continued CVD reductions to LDL-C levels <50 mg/dl, and to date, have yet exhibited a threshold below which there is no further benefit [12]. Furthermore, the long-term benefits from statins may be greater than suggested, due to greater LDL-C reductions, such that a 2-mmol/L decrease would result in CVD reductions of 36 % [30•]. Also, most trials utilize first-year CV events in their analysis of statin therapy, which do not represent the full statin effect and thus underestimate the complete benefit of the therapy [29, 51]. CTT data established a continuous improvement with a 1-mmol/L reduction in LDL-C from 22–25 % at 1 year, to 32 % at 3 years, 36 % at 5 years, and 40 % beyond 5 years [28, 29, 51, 52].

A 2009–10 NHANES evaluation showed similar data to 2005–06, with only 64 % of those with hyperlipidemia having reached their LDL-C goal, and of those with CVD or diabetes, only about one-third at their goal level. [53] However, even in those meeting their LDL-C goals, many still exhibit residual CV events. In the Turkish Adult Risk Factor Study (TARFS), metabolic syndrome was a major predictor of CHD in those with lower LDL-C, such that the presence of metabolic syndrome represents a specific cohort for those at continued risk for CVE [54].

The number of circulating LDL particles (LDL-P), either measured by serum apolipoprotein B (apoB) or indirectly by nuclear magnetic resonance (NMR) spectroscopy have been shown to be superior in head to head comparisons with both LDL-C and non-HDL as a marker of CV risk [55]. Both the Framingham-Offspring Study and MESA trials have demonstrated that increased LDL particle number portends a greater CV risk when LDL levels are lowered below 80 mg/dl [56, 57]. In a meta-analysis of statin trials where LDL-C levels were < 80 mg/dl with treatment, over 30 % had discordance between LDL-C and apoB, thus often presenting a false sense of security when achieving the recommended goal for LDL-C [58•] (Table 2). The increase in CVD risk occurs when the population percentile of LDL particle numbers, either measured by apoB or NMR, is greater than LDL-C [56].

Table 2 Discordance LDL, non-HDL & apoB in Trials Achieving LDL < 80 mg/dl [58•]
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In the Framingham offpring study, the LDL-P number exhibited significant variation in diabetics, even when achieving LDL-C levels < 50 mg/dl, and this was notable when triglyceride levels increased from 61 to 102 mg/dl [57]. Thus, even with attainment of LDL < 50 mg/dl and non-HDL < 80 mg/dl, 84 % and 92 % had LDL particles > 500 nmol/L, respectively [57]. The Monet trial included obese menopausal women, demonstrated only apoB and not LDL-C or non-HDL-C, and was a strong and independent predictor of inflammatory markers such as CRP and insulin resistance [58•]. This supports the concept that subendothelial lipoprotein retention with apoB particles initiates the maladaptive inflammatory response noted in atherosclerosis [59].

The discordance of LDL-P > LDL-C is strongly linked to all five metabolic syndrome biomarkers, supporting the use of metabolic syndrome as a reasonable surrogate for LDL-P > LDL-C [60]. In an analysis of 18 statin trials, statins reduced LDL-C and non-HDL-C to a greater extent than they lowered apoB or LDL-P, thus often achieving target LDL-C levels but not reaching the equivalent targets for apoB or LDL-P [61]. To underscore the significance of discordance between LDL-P and LDL-C, it has been suggested that aggressively treating subjects with statins using apoB > 70th percentile as a cut-off point for the US adult population, rather than LDL-C or non-HDL-C at the same population percentiles, could result in approximately 300,000 or 500,000 less CV events, respectively, over a decade [62, 63].

Where do we go from here?

The concepts presented suggest that the current obesity epidemic, when associated with an inflammatory, dysmetabolic state, are partly responsible for the century-long scourge that is CVD. In addition, during the past 40 years climate change associated with an increase in particulate matter in the atmosphere has exacerbated those risks incurred by those within the obesity, dysmetabolic, inflammatory milieu [41].

Recent recommendations from the AHA to improve CV health required meeting seven metrics: non-smoker, BMI < 25 kg/m2, ≥ 150 minutes of moderate exercise per week, DASH-type diet, untreated TC < 200 mg/dl, untreated BP < 120/80 and FBG < 100 mg/d [64]. NHANES data found that only 1.2 % of US adults in 2005–2009 met all seven goals for the promotion of cardiovascular health: [64] As noted, combining the concepts of statin therapy for continued lowering of LDL-C to current goals and beyond, treating for time spans longer than a few years, and improving statin adherence and compliance can all result in reducing CVD events to a far greater degree than typically expected [12, 51]. Given that the LDL-C range for a healthy neonate is 40–70 mg/dl and that an LDL-C of 70 mg/dl represents the 8th percentile for the adult US NHANES III population, it is evident that very few Americans will receive the benefits attributed to a lifetime of low LDL-C [65, 66].

The 30-year lipid trends show LDL-C levels decreasing from 134 to 117 mg/dl, while triglyceride levels have increased from 137 to 146 mg/dl [67]. These trends represent both sides of the CVD-risk debate, with decreasing LDL-Cs representing the statin effect and increasing triglycerides representing the obesity and metabolic syndrome epidemic [68, 69]. Given these conflicting outcomes, how can statin therapy be fine-tuned to better address those not being treated or those at high residual risk?

NHANES data shows that 7 % of the US population has a triglyceride level > 200 mg/dl and HDL < 40 mg/dl (men) or < 50 mg/dl (women), which is increased to 15 % in the diabetic population [66]. Individuals with a ratio of TG/HDL > 3.8 have an 80 % chance of forming a significant amount of small dense LDL-C particles, which establishes the discordant LDL-P > LDL-C. [67, 68] In a trial of 170 subjects with incident CHD who presented with LDL-C levels at goal (mean 73 mg/dl), a high TG/HDL ratio contributed strongly and remained predictive for residual CHD risk even when baseline LDL-C < 70 mg/dl [70]. In a meta-analysis of seven trials where LDL-C levels were < 70 mg/dl and 98 % of subjects were treated with statin therapy, 20 % exhibited plaque progression when evaluated with intravascular ultrasound [71]. In this study, those who had plaque progression had higher apoB levels, higher triglyceride levels and higher CRP levels at follow-up, suggesting that increased particle numbers played a role in the further progression of atherosclerosis despite statin therapy lowering LDL-C < 70 mg/dl (58.4 mg/dl and 56.5 mg/dl in the progression and non-progression groups, respectively) [72•].

How do climate change and air pollution integrate into the CVD risk spectrum? Studies have indicated that exposure to air pollutants, particularly fine particles < 2.5 μm (PM2.5) from vehicle emissions, coal burning, and industrial processes can be inhaled deeply into the lung with a portion depositing in the alveoli, ultimately resulting in systemic inflammation [35, 39, 73]. It has also been demonstrated that those who are obese and dysmetabolic appear to be more vulnerable to the inflammatory effects of PM2.5., such that the ambient air that millions of Americans are exposed to daily may contribute on a much greater scale to CV risk than that of second-hand cigarette smoke [41, 74, 75].

There remain concerns regarding the evidence base to support how aggressively to lower LDL-C, as well as the benefits from increasing the statin dosage [58•]. In both primary and secondary prevention trials, there remains considerable CVD residual risk in those treated to goal. O’Keefe has speculated that to achieve maximum benefit from LDL-C lowering, one would need to achieve an LDL-C of 57 mg/dl for primary prevention and 30 mg/dl for secondary prevention [65]. These goals were based on LDL-C and not LDL-P, such that those with cholesterol-poor, small dense LDL-C particles may require as much as 70 % or more particles to carry the same amount of LDL-C, and thus result in LDL-C thresholds even lower than those proposed by O’Keefe [65].

From a practical perspective, does consideration of this deadly quartet of obesity, metabolic syndrome, inflammation, and air pollution alter our approach to our patients? And if so, how might we address this issue since the quartet’s risk factors have worsened, rather than improved, over the past decade, with weight gain and sedentary lifestyles leading the way [6] (Figure 3)?

Fig. 3
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Prevalence of Non-lipid CVD Risk Factors in USA

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Specific interventions for each of the quartet’s risk factors have resulted in mixed results. For example, long-term weight management has not been shown to reduce CV mortality or morbidity, with the exception of bariatric surgery for those who are morbidly obese [75]. Concerns regarding different criteria used to define metabolic syndrome, as well as a lack of evidence to support its prognostic significance beyond its individual components, have raised questions about the relevance of the syndrome, per se [76, 77]. Issues regarding inflammatory markers, including CRP, as a causative factor in atherothrombosis are still being heavily contested [78]. No clinical trial to date has directly evaluated whether solo targeting of inflammation will reduce CV risk. The Cardiovascular Inflammation Reduction Trial (CIRT) will test this inflammatory hypothesis by evaluating the effect of low-dose methotrexate on patients with evident CVD [79]. Lastly, there is an ongoing debate as to the effects of climate change and particulate matter in the atmosphere and its potential effects on subsequent CVD [32•, 33-36].

Using the obesity epidemic as the focus of this discussion, we have demonstrated the interconnectivity of central or visceral obesity with metabolic dysregulation, leading to a subclinical inflammatory process that ultimately results in atherosclerosis and CV events. The presence of increased atmospheric PM2.5 appears to exacerbate this risk in those manifesting these risk factors. A harbinger of risk that facilitates this process is the LDL particle, which can be discordant with the standard bearer of LDL-C. . As one becomes more dysmetabolic with more metabolic risk factors, the chance of divergence between LDL-C and LDL-P also increases [56, 63]. In a meta-analysis of patients with coronary plaque who achieved LDL-C levels < 70 mg/dl, it was noted that higher levels of on-treatment triglycerides, apoB, and CRP helped distinguish those in whom plaque progressed [72•]. Although body weights were similar in both those who did and did not progress (BMI 31.2 vs. 30.9 kg/m2), metabolic syndrome was somewhat more prominent in the 59 % who progressed compared to the 55 % who did not progress. Of interest in this analysis is the fact that both those who did and did not progress were obese, and that for those who progressed, the associated metabolic, inflammatory environment was more common.

The American Association of Clinical Chemists advocated for apoB and LDL-particles to be included in CVD screening and treatment guidelines [55]. This concept was endorsed and adopted by both the Canadian and European guidelines [80, 81] The International Guideline Center recommended a modified therapeutic algorithm that included both NMR LDL-P and apo B [83] (Table 3). These augmented recommendations may require more robust LDL-C lowering to attain the therapeutic goals set for LDL particles [80–82]. Also, consistent with the Canadian guidelines, in subjects at high risk for CVD with a baseline LDL < 70 mg/dl, lowering LDL-C by 50 % is recommended [80]. Although concerns exist related to the use of apoB for routine testing, such as additional cost, provider unfamiliarity, and less well-defined targets, it appears that those manifesting this quartet of risk factors, especially if already treated with statins, may benefit from this modified treatment alogorithm [83].

Table 3 Suggested LDL-C and LDL-P Goals
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Summary

It would be reasonable to surmise that an individual who is obese or overweight, and who manifests a dysmetabolic state and/or subclinical inflammation is very likely to be at increased CV risk even when his or her LDL-C levels are at goal. Additionally, this risk may be exacerbated in the 25–50 % of Americans who reside in communities with increased exposure to unhealthful short term and/or year-round levels of particulate pollution or ozone in the atmosphere. [84] A recent WHO measurement of the global burden of disease from 2010 found that four of the top ten global causes for disability-adjusted life years (DALYs) were (1) household air pollution from solid fuels, (2) high BMI, (3) exposure to ambient particulate matter pollution, and (4) physical inactivity, all of which contribute to the number-one global cause for mortality, ischemic heart disease [85]..

In individuals with this deadly quartet of obesity, dysmetabolic state, subclinical inflammation, and exposure to unhealthy levels of particulate matter, employing an aggressive lifestyle intervention is a crucial initial step to positively impacting CVD risk. However, beyond the scope of this discussion, it should be noted that exercise regimes that achieve > 9 METS on an exercise tolerance test, independent of weight loss, have been shown to reduce cardiovascular mortality [24, 30•].

This review highlights statin’s role in lowering CV risk in those with obesity, metabolic syndrome and subclinical inflammation, independent of baseline LDL-C levels. Since air pollution is ubiquitous, it has not been the focus of any specific trial; however, given the CVD-associated benefits of statin treatment in those who resided in areas of higher PM2.5, it may be reasonable to extrapolate the statin benefit in those presenting with all four components of the quartet.

Furthermore, there is compelling data that more aggressive statin treatment to lower LDL-C levels beyond current guidelines in patients with this quartet will further reduce LDL particles, which may be elevated even when LDL-C is at goal. Surrogate markers for increased LDL particles include elevated triglyceride levels or elevated triglyceride/HDL ratios (> 3.8), and may represent a cohort of approximately 30 % of adults who may have discordance between LDL-C /non-HDL-C and apoB/ LDL particle number [56, 62, 70]. This discordance may very well represent a disproportional number of individuals with this quartet of CVD risk factors who manifest residual CV risk even when treated to LDL-C goal.

Other risk factors, such as inactivity, sleep disorders, stress, depression, excessive alcohol intake, and smoking, may also contribute to residual CVD risk, as they have also been independently associated with a subclinical inflammatory state [31].

Additional studies are needed to address the question of whether certain types of obesity are more vulnerable to external stimuli and whether these environmental stressors have an additive cytokine response that further exacerbates CV risk. Finally, and the crux of this discussion, does a more aggressive approach focused on lowering LDL particles via statin treatment make sense for those with this quartet of risk factors, to ultimately result in decreasing the residual CVD risk?