The associations between exercise and lipid biomarkers

doi:10.1016/j.pcad.2022.11.004

Progress in Cardiovascular Diseases

Volume 75, November–December 2022, Pages 59-68

https://doi.org/10.1016/j.pcad.2022.11.004 Get rights and content

Abstract

Cardiovascular diseases (CVD) remain the leading cause of death globally, and further efforts are being undertaken to understand and modify CVD risk factors, such as dyslipidemia (DLD), hypertension, and diabetes. The sedentary lifestyle of most individuals today contributes to the prevalence of these conditions. Uncontrolled dyslipidemia serves as a fertile ground for atherosclerotic plaque formation, while lipoproteins (Lp) act as cofactors for inflammatory processes that cause plaque destabilization leading to subsequent CVD events. As such, many health experts and institutions continue to emphasize the importance of cardiorespiratory fitness (CRF) and muscular strength (MusS) with the intent to reduce atherogenic lipoproteins and proprotein convertase subtilisin kexin type 9 (PCSK-9) expression. Concordantly, the two modes of exercise training (ET), such as aerobic ET (aET) and resistance ET (rET) have both demonstrated to improve CRF and MusS, respectively. Although both modes of ET were shown to independently reduce mortality, participation in both forms resulted in a more pronounced improvement in cholesterol levels and CVD-related mortality. Though reduction of adiposity is not a pre-requisite to achieve better control of DLD through increased CRF and MusS, the beneficial effects of physical activity on the inflammatory processes linked to atherosclerosis are almost always associated with a simultaneous decrease in overall adiposity. It is therefore essential to promote both aET and rET, including weight loss in order to attenuate the risks stemming from atherosclerosis and its proinflammatory components.

Introduction

Coronary heart disease (CHD) is the leading cause of death in the United States (US), which is strongly associated with the progression of dyslipidemia (DLD.) In the US with a population of about 332 million, nearly a third (n = 94 million) have total cholesterol (TC) levels above 200 mg/dL, which is a 12% increase from the period of 2015 to 2018 according to the 2021 Heart Disease and Stroke Statistics.¹^,² According to the 2017 Update of Heart Disease and Stroke Statistics, at least a third of Americans have DLD, which is classified as either primary (familial) DLD or secondary (acquired) DLD.² Primary DLD is predominantly due to inheritable genetic disorders, whereas secondary DLD is caused by, but not limited to, medications (such as steroids and amiodarone), underlying medical conditions, such as obesity, hypothyroidism, diabetes mellitus (DM), and a sedentary lifestyle.³

Although there are various effective anti-hypercholesterolemic drugs that are available on the market, effective ET has been shown to decrease cardiovascular disease (CVD)-related mortality by as much as 20 to 30%.⁴ Unfortunately, the promotion of exercise training (ET) has been significantly underutilized in many clinical settings.⁵ In clinical practice, the degree of DLD and its response to ET can be effectively analyzed by having an adequate understanding of its relationship with lipid and high-sensitivity C-reactive protein (hs-CRP) levels.

The focus of this review is to clarify (1) the clinical impact of lipid biomarkers on CVD outcomes, (2) the semantics in ET, (3) the impact of ET on CVD outcomes and mortality, (4) the impact of ET on lipoproteins, (5) therapeutic strategies for DLD, (6) the significance of emerging studies on DLD and ET, as well as (7) the current ET guidelines that are globally accepted for the primary and secondary prevention of CVD and mortality.

Section snippets

The impact of lipid biomarkers on CVD outcomes and mortality

The lipid profile, as well as inflammatory markers, constitute the umbrella term for lipid biomarkers. Notably, the lipid profile can be divided into two categories, namely, lipids-proper [such as fatty acids (FAs) and triglycerides (TGs)] and lipoproteins [such as low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), very-low-density-lipoprotein cholesterol (VLDL-C), and lipoprotein-a [Lp(a)], etc.⁶

There are broadly accepted studies elucidating how low

The semantics in ET

In establishing the impact of activity upon various dependent clinical variables, particular terms may be defined and used. Physical activity (PA) is a broad term for energy-expending bodily movements. On the other hand, ET is the regimented utilization or habitual use of PA that generally results in improvements in levels of cardiorespiratory fitness (CRF), which is perhaps the strongest predictor of CVD and all-cause survival. A meta-analysis by Laukkanen et al. found that an increase in CRF

The impact of ET on CVD and mortality

The American Heart Association (AHA) now considers CRF as an important vital sign as it can be clinically measured by means of VO₂max or METs estimation.¹⁵^,²³^,²⁴^,²⁸ A meta-analysis by Kodama et al. reported that a single-unit rise in tolerable PA measured in METs was correlated with a reduction in all-cause mortality by 13% and CHD/CVD events by 15%.²⁹ Lyerly et al. also found that even in high-risk populations, such as in women (n = 3044) with impaired fasting glucose and DM, higher fitness or

The impact of ET on lipid biomarkers

Given that DLD and ET seemingly have opposite implications on CVD outcomes and mortality, there are many studies demonstrating an inverse relationship between ET with apoB-containing lipoproteins besides ET's favorable impact on HDL-C. Both of the studies by Blair et al. and Sui et al., which are decades apart, showed that sequential improvements in CRF resulted in incremental decreases in the risk of developing DLD.⁴⁸^,⁴⁹ In 2019, Lavie et al. were able to tabulate the reported impact of

Mechanisms of lipid attenuation in aET

During aET or fasting states, the plasma apoC2 apolipoprotein moiety is transferred onto TG-rich lipoproteins (TRL) resulting in an activation cascade of lipoprotein lipases (LP) on endothelial surfaces, which in turn hydrolyzes TG components in TRLs, which are then exchanged for cholesterol esters (CE) from HDL-C molecules. Mediated by CE transport proteins (CETP), this causes a substantial reduction in TRL-particle size. TRLs with depleted TG stores become reclassified as lipoprotein remnants

Baseline and trajectory levels in dyslipidemia

Many studies have confirmed that individuals with higher baseline atherogenic lipids who had undergone ET, often experience improvements in non-HDL-C levels at a higher degree.⁷¹^,77, 78, 79 Aside from baseline levels, the age and chronicity of atherogenic Lp is just as important when predicting risk of CVD and mortality.¹⁴ That being said, the lifetime risk of developing CHD is much greater in younger populations who have elevated TC.⁸⁰ Those who had successfully maintained very low levels of

ET and HS-CRP

Inflammatory processes were noted from thromboembolic episodes in the setting of atherosclerosis. Hs-CRP is an acute phase reactant useful for predicting CVD-related events and the most widely used acute nonspecific inflammatory marker. As such, it is also associated with other diseases including HTN, DM, CVA, acute coronary syndrome (ACS), and peripheral arterial occlusive disease.¹⁵^,⁸³ At >3 mg/L, it is independently associated with CHD and can be used to monitor therapeutic response

Mechanism of HS-CRP attenuation during rET

Although there is lack of clarity as to how ET directly attenuates hs-CRP, skeletal muscle is known to secrete IL-6 in response to muscle contraction. This creates an anti-inflammatory environment by the production of IL-1ra and IL-10, which are both anti-inflammatory cytokines. The levels of IL-6 secreted is dependent on the amount of skeletal muscle recruited, which can be optimized by training muscle groups at high speeds/volumes/intensities/numbers (such as rET). Such anti-inflammatory

Lp(a) and PCSK-9 and their role in ET

Due to its LDL-like core, Lp(a) is acknowledged as an atherogenic protein. This core contains an apoB component forming a disulfide bond with the exterior of Lp(a)’s heavily glycosylated apolipoprotein(a) [Apo(a)]. In contrast, oxidized phospholipids (OxPL) bind to the external apo(a) moiety resulting in the upregulation of interleukin-8 (IL-8) mRNA and protein expression on atherogenic macrophages.110, 111, 112

Compared to patients with stable disease, culprit lesions of patients with unstable

ET guideline review

As defined by the World Health Organization, 1 MET is the basal caloric expenditure of an individual while sitting, which is equivalent to 1 kcal/kg/h. Moderate PA ranges from 3 to 6 METs whereas high-intensity PA is often >6 METs.¹²⁵

According to the 2018 US Department of Health and Human Services PAG for Americans, 2nd edition and the 2019 American College of Cardiology (ACC)/AHA, the recommended levels of PA should be at least moderate in intensity (3 to 5.9 METs) for about 150 min per week

Conclusions

Largely driven by the shift to automated services, sedentary lifestyles have further driven the obesity epidemic, and rise in DLD and other associated CVD comorbidities. DLD, a modifiable CVD risk factor, serves as a fertile ground for atherosclerotic lesions that can be destabilized by co-inflammatory processes resulting in distal clot migration and other related CVD events. Several studies have shown aET and rET can improve CRF and MusS, respectively. By improving lipid profiles

Financial support and sponsorships

None.

Declaration of Competing Interest

None.

Acknowledgement

The authors of this study would like to acknowledge Therese F. Posas-Mendoza, MD for editing and peer-proofreading this manuscript.

References (129)

G.F. Fletcher et al.
Promoting physical activity and exercise: JACC health promotion series
J Am Coll Cardiol
(2018 Oct 2)
M. Cicoira et al.
Skeletal muscle mass independently predicts peak oxygen consumption and ventilatory response during exercise in noncachectic patients with chronic heart failure
J Am Coll Cardiol
(2001 Jun 15)
Y.M.M. Park et al.
The effect of cardiorespiratory fitness on age-related lipids and lipoproteins
J Am Coll Cardiol
(2015 May 19)
B.A. Ference et al.
Impact of lipids on cardiovascular health: JACC health promotion series
J Am Coll Cardiol
(2018 Sep 4)
J.A. Laukkanen et al.
Objectively assessed cardiorespiratory fitness and all-cause mortality risk: an updated Meta-analysis of 37 cohort studies involving 2,258,029 participants
Mayo Clin Proc
(2022 Jun)
C.J. Lavie et al.
Making the case to measure and improve cardiorespiratory fitness in routine clinical practice
Mayo Clin Proc
(2022 Jun)
P. Kokkinos et al.
Cardiorespiratory fitness and mortality risk across the spectra of age, race, and sex
J Am Coll Cardiol
(2022 Aug 9)
C.J. Lavie et al.
Fit is it for longevity across populations
J Am Coll Cardiol
(2022 Aug 9)
C. Ozemek et al.
An update on the role of cardiorespiratory fitness, structured exercise and lifestyle physical activity in preventing cardiovascular disease and health risk
Prog Cardiovasc Dis
(2018 Dec)
G.W. Lyerly et al.
The association between cardiorespiratory fitness and risk of all-cause mortality among women with impaired fasting glucose or undiagnosed diabetes mellitus
Mayo Clin Proc
(2009 Sep)

P.F. Kokkinos et al.

Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study

Lancet Lond Engl

(2013 Feb 2)

G.A. Kelley et al.

Aerobic exercise and HDL2-C: a meta-analysis of randomized controlled trials

Atherosclerosis.

(2006 Jan)

E.A. Bakker et al.

Association of Resistance Exercise with the incidence of hypercholesterolemia in men

Mayo Clin Proc

(2018 Apr)

L.A. Kaminsky et al.

Cardiorespiratory fitness and cardiovascular disease - the past, present, and future

Prog Cardiovasc Dis

(2019 Apr)

X. Sui et al.

Impact of changes in cardiorespiratory fitness on hypertension, dyslipidemia and survival: an overview of the epidemiological evidence

Prog Cardiovasc Dis

(2017 Jul)

C.J. Lavie et al.

Impact of fitness and changes in fitness on lipids and survival

Prog Cardiovasc Dis

(2019 Oct)

C.M. Yu et al.

Long-term changes in exercise capacity, quality of life, body anthropometry, and lipid profiles after a cardiac rehabilitation program in obese patients with coronary heart disease

Am J Cardiol

(2003 Feb 1)

B. Marti et al.

Effects of long-term, self-monitored exercise on the serum lipoprotein and apolipoprotein profile in middle-aged men

Atherosclerosis.

(1990 Feb)

C.D. Lee et al.

Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men

Am J Clin Nutr

(1999 Mar)

A. Halverstadt et al.

Endurance exercise training raises high-density lipoprotein cholesterol and lowers small low-density lipoprotein and very low-density lipoprotein independent of body fat phenotypes in older men and women

Metabolism.

(2007 Apr)

A. Pascot et al.

Reduced HDL particle size as an additional feature of the atherogenic dyslipidemia of abdominal obesity

J Lipid Res

(2001 Dec)

D.T. Ko et al.

High-density lipoprotein cholesterol and cause-specific mortality in individuals without previous cardiovascular conditions: the CANHEART study

J Am Coll Cardiol

(2016 Nov 8)

A. Wolska et al.

Apolipoprotein C-II: new findings related to genetics, biochemistry, and role in triglyceride metabolism

Atherosclerosis.

(2017 Dec)

B.J. Nicklas et al.

Increases in high-density lipoprotein cholesterol with endurance exercise training are blunted in obese compared with lean men

Metabolism.

(1997 May)

J. Bergeron et al.

Race differences in the response of postheparin plasma lipoprotein lipase and hepatic lipase activities to endurance exercise training in men: results from the HERITAGE family study

Atherosclerosis.

(2001 Dec)

C.B. Breneman et al.

The impact of cardiorespiratory fitness levels on the risk of developing Atherogenic dyslipidemia

Am J Med

(2016 Oct)

C.J. Lavie et al.

Effects of cardiac rehabilitation and exercise training on low-density lipoprotein cholesterol in patients with hypertriglyceridemia and coronary artery disease

Am J Cardiol

(1994 Dec 15)

C.J. Lavie et al.

Effects of nonpharmacologic therapy with cardiac rehabilitation and exercise training in patients with low levels of high-density lipoprotein cholesterol

Am J Cardiol

(1996 Dec 1)

C.J. Lavie et al.

C-reactive protein and cardiovascular diseases--is it ready for primetime?

Am J Med Sci

(2009 Dec)

J.S. Flier

The adipocyte: storage depot or node on the energy information superhighway?

Cell.

(1995 Jan 13)

M.A. Albert et al.

Effect of physical activity on serum C-reactive protein

Am J Cardiol

(2004 Jan 15)

C.J. Lavie et al.

The obesity paradox, weight loss, and coronary disease

Am J Med

(2009 Dec)

T.L. Hammonds et al.

Effects of exercise on c-reactive protein in healthy patients and in patients with heart disease: a meta-analysis

Heart Lung J Crit Care

(2016 Jun)

World Bank

World Development Indicators [Internet]

(2022)

S.S. Virani et al.

Heart disease and stroke Statistics-2021 update: a report from the American Heart Association

Circulation.

(2021 Feb 23)

M.F. Hill et al.

Hyperlipidemia

M.V.F. Mendoza et al.

The Effects of Exercise on Lipid

P.W. Wilson et al.

Prediction of coronary heart disease using risk factor categories

Circulation.

(1998 May 12)

S.E. Nissen et al.

Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial

JAMA.

(2006 Apr 5)

K.M. Anderson et al.

Cholesterol and mortality. 30 years of follow-up from the Framingham study

JAMA.

(1987 Apr 24)

J.P. Vaara et al.

Associations of maximal strength and muscular endurance with cardiovascular risk factors

Int J Sports Med

(2014 Apr)

C. Li et al.

Does the association of the triglyceride to high-density lipoprotein cholesterol ratio with fasting serum insulin differ by race/ethnicity?

Cardiovasc Diabetol

(2008 Feb)

S.E. Nissen et al.

Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease

N Engl J Med

(2005 Jan 6)

C.J. Lavie et al.

Impact of physical activity, cardiorespiratory fitness, and exercise training on markers of inflammation

J Cardiopulm Rehabil Prev

(2011 Jun)

P.M. Ridker et al.

C-reactive protein levels and outcomes after statin therapy

N Engl J Med

(2005 Jun 6)

D.A. Morrow et al.

Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor trial

Circulation.

(2006 Jul 25)

R. Kones

Rosuvastatin, inflammation, C-reactive protein, JUPITER, and primary prevention of cardiovascular disease--a perspective

Drug Des Devel Ther

(2010 Dec)

C.J. Lavie et al.

Sedentary behavior, exercise, and cardiovascular health

Circ Res

(2019 Mar)

D.L. Swift et al.

Physical activity, cardiorespiratory fitness, and exercise training in primary and secondary coronary prevention

Circ J Off J Jpn Circ Soc

(2013)

D. Brennan

What Is a MET Score? [Internet]

Cited by (10)

Over a decade as editor-in-chief at Progress in Cardiovascular Diseases
2024, Progress in Cardiovascular Diseases
Low Cholesterol and Valvular Heart Disease Mortality: Another Cardiovascular Paradox
2023, American Journal of Cardiology
Cardiovascular statistics 2023
2023, Progress in Cardiovascular Diseases
Walking 200 min per day keeps the bariatric surgeon away
2023, Heliyon
Exercise and increased physical activity are vital components of the standard treatment guidelines for many chronic diseases such as diabetes, obesity and cardiovascular disease. Although strenuous exercise cannot be recommended to people with numerous chronic conditions, walking is something most people can perform. In comparison to high-intensity training, the metabolic consequences of low-intensity walking have been less well studied. We present here a feasibility study of a subject who performed an exercise intervention of low-intensity, non-fatiguing walking on a deskmill/treadmill for 200 min daily, approximately the average time a German spends watching television per day. This low-impact physical activity has the advantages that it can be done while performing other tasks such as reading or watching TV, and it can be recommended to obese patients or patients with heart disease. We find that this intervention led to substantial weight loss, comparable to that of bariatric surgery. To study the metabolic changes caused by this intervention, we performed an in-depth metabolomic profiling of the blood both directly after walking to assess the acute changes, as well as 1.5 days after physical activity to identify the long-term effects that persist. We find changes in acylcarnitine levels suggesting that walking activates fatty acid beta oxidation, and that this mitochondrial reprogramming is still visible 1.5 days post-walking. We also find that walking mildly increases gut permeability, leading to increased exposure of the blood to metabolites from the gut microbiome. Overall, these data provide a starting point for designing future intervention studies with larger cohorts.
Long-term continuous exercise training counteracts the negative impact of the menopause transition on cardiometabolic health in hypertensive women - a 9-year RCT follow-up
2023, Progress in Cardiovascular Diseases
The study examined effects of 9-yrs of multicomponent exercise training during the menopause interval on cardiometabolic health in hypertensive women.
Sedentary, middle-aged women (n = 25) with mild-to-moderate arterial hypertension were randomized into a soccer training (multicomponent exercise; EX; n = 12) or control group (CON; n = 13). EX took part in 1-h football training sessions, 1–3 times weekly, for a consecutive 9-years, totaling ∼800 training sessions, while CON did not take part in regular exercise training. 22 participants entered menopause during the intervention.
A time×group interaction effect (P = 0.04) of 8.5 mmHg in favour of EX was observed for changes in mean arterial pressure (MAP) (EX: −4.8 [−10.7;1.1] mmHg, CON +3.7 [−2.0;9.3] mmHg). Time×group interaction effects in favour of EX were also observed for total body weight (4.6 kg, P = 0.008, EX: +0.7 [−1.7;3.0] kg, CON: +5.3 [3.0;7.6] kg, total fat percentage (5.7%-points, P = 0.02; EX (−1.9 [−4.4;0.6] %-points; P = 0.13), CON +3.8 [1.4;6.2] %-points and for total cholesterol (1.2 mmol/l, P = 0.03, EX: −0.5 [−1.0;-0.1] mmol/l, CON: +0.7 [0.2;1.1] mmol/l. EX reduced (P = 0.02) plasma low-density lipoprotein cholesterol by −0.4 [−0.8;-0.1] mmol/l, whereas an increase (P = 0.01) of 0.4 [0.1;0.8] mmol/l occurred in CON (interaction. P < 0.001). A time×group interaction (P = 0.004) existed for changes in exercise capacity in favour of EX. Fasting glucose remained unchanged in EX and increased (P < 0.001) by 0.7 [0.4;1.0] mmol/l in CON (time×group interaction P = 0.02).
In conclusion, long-term multicomponent exercise training fully counteracts the detrimental effects of the menopause transition on cardiometabolic health in hypertensive women.
A decade as editor-in-chief of progress in cardiovascular diseases
2023, Progress in Cardiovascular Diseases

View all citing articles on Scopus

View full text