The impact of nontraditional lipid profiles on left ventricular geometric abnormalities in general Chinese population

Left ventricular hypertrophy (LVH), a potent marker of end-organ damage, is an independent predictor and potentially modifiable risk factor for coronary heart disease (CHD), heart failure (HF), and other major cardiovascular (CV) morbidity and mortality [1, 2]. In light of left ventricular mass index (LVMI) along with relative wall thickness (RWT), four distinct patterns of left ventricular (LV) geometry are further proposed to explain the pathophysiologic basis for cardiac remodeling, with concentric LVH conferring a stronger prognostic value of morbid CV events [3, 4]. Although greater left ventricular mass (LVM) might initially be considered beneficial by a concomitant LV wall stress reduction and avoidance of hemodynamic compromise, in long-term, the progression of LV geometric abnormalities, particularly LVH, can prove to be maladaptive and portend a poor prognosis [5–7]. Identification and intervention of the CV risk factors underlying a specific phenotype of LV geometry before development of manifest disease are of paramount importance, given that knowledge of these geometric adaptations has been a fundamental precursor of CV disorders.

Reports from observational studies on the possibility of dyslipidemia-induced LV remodeling have been inconsistent [8–16]. Several lines of evidence have demonstrated that low high-density lipoprotein cholesterol (HDL-C) may unfavorably modify LV structure in the setting of elevated LVM or presence of LVH [8–10], whereas others have not [11–13]. Historically, there were conflicting data as to whether greater total cholesterol (TC) has been implicated in increased LVM [15, 16]. It was also plausible that alterations in LV morphology would be related at least in part to the excess of triglyceride (TG) which favors a high LVM-to-volume ratio and LV end-diastolic volume [12]. Conversely, lipid derangements, represented as cholesterol remnants and TG, were insufficient to cause an overt increase in LVM and LV wall thickness [16]. Recent emphasis has been placed in the clinical implications of nontraditional lipid profiles as powerful and independent predictors of cardiovascular disease (CVD) outcomes [17–21]. For instance, previous studies revealed that TC/HDL-C ratio could represent a simple atherogenic particle burden tool informing on lipoprotein particle concentration and size not available in cholesterol-based measurements [22, 23]. Notably, TC/HDL-C ratio offered significant incremental prognostic information over low-density lipoprotein cholesterol (LDL-C) and non-HDL-C for predicting CVD events [18, 20, 24]. Moreover, TG/HDL-C ratio has received growing interest in identifying insulin resistance and concentrations of sd-LDL particles as a novel, inexpensive, and readily available biomarker for quantifying atherogenic and cardiometabolic risk [17, 19, 25, 26]. Further, assessment of lipid metabolism and atherosclerotic status using a simple tool, such as LDL-C/HDL-C ratio, not only could help closely reflecting the interactions between lipid fractions but also could better predict plasma atherogenicity than isolated lipid values [18, 27, 28]. It has recently been proposed that non-HDL-C that includes all of the atherogenic lipoproteins, such as TG-rich lipoproteins, intermediate-density lipoprotein cholesterol, LDL-C, and lipoprotein(a) could better predict cardiovascular outcomes in patients on LDL-C-lowering therapy [20, 24].

To date, data are sparse regarding the relative performance of nontraditional lipid profiles for the purpose of reclassification of LV geometry risk. Di Bonito P et al. advocated that a high TG/HDL-C ratio, independent of blood pressure and visceral adiposity, was a key determinant of worrisome concentric LVH [29]. Interestingly, an epidemiological investigation from the Framingham Heart Study did not support an independent correlation of non-HDL-C and LV remodeling [11]. In this regard, it is likely that the adverse impacts of nontraditional lipid profiles on CVD incidence may partly be mediated by it adverse effects on LV structural remodeling. However, no prior work has examined this premise comprehensively. We hypothesized that evaluating the influence of nontraditional lipid profiles on the probability of subclinical LV geometry change is helpful to understand the pathogenesis of CVD related to dyslipidemia. Accordingly, the current study was initiated to examine the contribution of nontraditional lipid profiles (TC/HDL-C, TG/HDL-C, LDL-C/HDL-C, and non-HDL-C) to the prevalence of morphologic LV abnormalities in the general population of rural China.

The constellation of our findings offered novel evidence for an independent positive association of nontraditional lipid profiles (TC/HDL-C, TG/HDL-C, LDL-C/HDL-C, and non-HDL-C) with concentric LVH, a hallmark of preclinical CVD, in the general population of rural China. That is to say, elevated nontraditional lipid parameters levels were associated with increased risk of concentric LVH in a dose-response fashion and subsequently could be used to monitor programs aimed at mitigating adverse structural remodeling of the heart and identifying individuals at high risk for CVD. Our study further suggested that nontraditional lipid profiles lowering might yield benefits in concentric LVH prevention.

Nontraditional lipid profiles has been shown in numerous studies to be useful screening tools for various populations, identifying those with higher risk of subsequent CV complications and heart failure [17–21]. As anticipated from previous work, TC/HDL-C ratio, a more accurate parameter reflecting the features of the discordance between particle concentration and cholesterol content [22, 23], was instrumental in identifying coronary atheroma progression and cardiovascular events, as well as provided atherogenic lipid particles information, especially when apolipoprotein fractions, LDL-C, and non-HDL-C levels were discordant [18, 20, 24, 37]. TG/HDL-C ratio has proved itself to be an effective marker of proatherogenic small and dense LDL particles [25, 26], and thus of insulin resistance and poor cardiometabolic profile. This increased concentration of high risk particles is predictive of an augmented risk of CHD in multiethnic populations [17, 19]. Further, atherogenic metabolic disorders evaluated in LDL-C/HDL-C ratio was an excellent indicator of coronary lipid-rich plaque and early stage atherosclerosis [18, 28, 38]. Finally, there was also some evidence that non–HDL-C, in comparison to LDL-C, was more relevant to atherogenic lipoprotein subfractions and might be a potentially better index in evaluating the cardiovascular risk [18, 20, 21].

The degree of contribution of dyslipidemia to LV remodeling has been debated, with evidence both for and against the predictive utility of lipid concentrations on indexes of LV structure [8–16]. Hence, the adoption of nontraditional lipid profiles to estimate altered LV morphology has fostered a growing enthusiasm. Proposals to replace information on classic lipid risk factors with lipid ratios or a single index were motivated by the idea that nontraditional lipid profiles better represent the underlying atherosclerotic process. In a very large population of Italian outpatient children with overweight, Di Bonito P and coworkers concluded that TG/HDL-C ratio discriminated better than non-HDL-C with prevalent concentric LVH [29, 39]. Supporting this finding, LDL-C/HDL-C contributed to the origin of LVH included in a prospective longitudinal cohort study over 20-year period [40]. In that study, the odds ratio for LVH was 1.31 (95% CI: 1.02–1.67) after controlling for history of ischemic heart disease, valvular disease, and use of antihypertensive medication. Partially different findings emerged from Framingham Heart Study, where there was no meaningful relation of changes in LV structure with non-HDL-C levels [11]. On the other hand, experimental evidence suggested that hypercholesterolemia was noted to have a harmful effect on cardiac systolic and diastolic function, and LV remodeling in response to myocardial infarction (MI) [41, 42]. Indeed, investigators from the Framingham Heart Study identified dyslipidemia (indicated by elevated non-HDL-C) was known to promote the development of heart failure, with mildly attenuated effect size by adjusting interim MI [43]. This notion was further supported by the Multiethnic Study of Atherosclerosis (MESA) study that found the coexistence of high TC/HDL-C ratio with diabetes aggravated a program of HF risk [44]. We speculated that these correlations were probably partially attributable to the possible association of nontraditional lipid profiles with the prevalence of adverse cardiac remodeling. Abnormal LV geometry has been systematically discussed in the context of incident HF and believed to be related to worse prognosis and outcomes. It is now becoming evident that LV geometric abnormalities have been recognized as a cumulative indicator that reflects the severity and chronicity of cardiovascular risk factors, which highlights the need to develop a better risk stratification and tailored screening tool. In this sense, this middle-aged, cross-sectional, population-based design is initiated to examine and validate the practicality of nontraditional lipid profiles as the key correlates of LV geometric abnormalities in rural China.

The present study strengthened and extended the conclusions of some previous investigations on the predictive impact of dyslipidemia on morphological alterations of LV geometry. After taking into account a number of confounders, TC/HDL-C and TG/HDL-C increased the risk for presence of concentric LVH, while the probability of eccentric LVH only modestly increased in the presence of high TC/HDL-C, and was mainly explained by metabolic abnormalities. Similarly, LDL-C/HDL-C and non-HDL-C were associated with a pronounced increase in concentric LVH. The relation of these lipid ratios to eccentric LVH became nonsignificant when we adjusted for hypertension, diabetes, obesity, history of CVD, antihypertensive and antidiabetic medication use, and we contemplated that its effects may partly be accountable to these conditions. These results were not in accord with the prior findings of Framingham Heart Study, potentially due to significant differences in the ethnicity and the age range of the studied population. Our conclusions may be clinically relevant because changes in LV geometry, specifically concentric LVH, have typically been appreciated as an important predictor of a greater risk of CV events.

There is a panel of plausible pathomechanisms responsible for the increased risk of abnormal LV geometry in those with poor nontraditional lipid profiles. HDL-C is regarded an important mediator of preventing myocardial lipid accumulation through reverse cholesterol transport, a process that involves elimination of free cholesterol by transferring and uptaking of free cholesterol from the peripheral tissues to the liver [45]. Inflammation has been a potential candidate for adverse LV remodeling [46], HDL-C exerted a protective effect by its anti-inflammatory properties [47]. Taken together, HDL-C was involved in improving endothelial function and weakening LDL oxidation, whereby protecting against cardiac and vascular remodeling [43]. These manifestations could be attributed to negative expression of cell surface adhesion molecules and inhibition of monocyte infiltration into the endothelium [48]. Secondly, under physiologic conditions of obesity and non-ischemic failing human hearts, increased stores of TGs were detectable in the myocardium [49]. The lipotoxic byproduct, generating from deleterious fatty acid pathways after myocardial TG overstorage entered a continuous cycle between hydrolysis and fatty acid esterification, resulted in the deterioration of cardiac function [50]. Thirdly, nontraditional lipid profile, such as TG/HDL-C, was a strong correlate of insulin resistance, which has been an important route leading to LVH [8–10]. Furthermore, excess cholesterol predisposes to vascular lesions, an early feature of arteries rigidity, which is a factor potentially to be the driving force behind increased LVM. Given the positive effect of systemic atherosclerosis on LVH, it is intriguing that relations were best described between nontraditional lipid indices and concentric LVH [51]. Thus, it is possible that abnormal LV geometry at that early stage of heart failure may be remediable to lipid-lowering therapy.

Our novel investigations have crucial clinical and public health implications for pointing out that those with high levels of nontraditional lipid profiles had a significantly greater burden of adverse LV remodeling that begins as subclinical changes in cardiac structure and eventually progresses to clinical HF. The present study included a large community-based sample with an available comprehensive panel of lipid measurements and echocardiographic data in Northeast China. The simplicity and cost-effective of nontraditional lipid profiles have made it possible for application to large-scale clinical and epidemiological studies and evaluated LV geometry and its modification over time to CVD outcomes. Despite the aforementioned strengths, certain limitations merit consideration. The cross-sectional design allows for only determining an association of nontraditional lipid profiles with concentric LVH, but fails to imply a causal relationship and track changes in lipid concentrations over time. Further confirmations in prospective studies to assess the prognostic role of nontraditional lipid profiles in LV morphology are warranted. In addition, although echocardiography has been well validated for measuring indices of cardiac structure, cardiovascular magnetic resonance (CMR) is thought to be highly accurate, reproducible, and widely considered the gold standard for the assessment of ventricular size and function. Finally, our results are predominantly applicable to Chinese adults, which limit generalization to the broader racial or ethnic populations.

Nontraditional lipid profiles emerged as a valuable operational approach, a potential alternative to traditional lipid parameters, to refine risk stratification in individuals with concentric LVH. Under this scenario, these readily available lipid measurements could be applied as a relatively simple tool for subclinical signs of cardiac abnormalities assessment. The feasible benefit of aggressive primary prevention in combination lipid modifier therapy for adverse LV remodeling subjects with residual atherogenic dyslipidemia requires further investigation.