Reversal of CVD with diet and lifestyle

Among the ocean of research, I’m very interested in natural interventions which have reversed common diseases, since they help reveal basic ecology. Here’s a mini-review based around my initial reading of such CVD trials.

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 31% of all deaths (WHO). The most common forms are coronary artery and cerebrovascular diseases (affecting heart and brain, respectively) driven by atherosclerosis (i.e. plaque build-up) ^1,2. Further, CVD and intracranial atherosclerosis are also linked to dementia ^3,4, another leading cause of death (e.g. Dementia Hub).

Atherosclerosis is a highly prevalent and systemic disease, affecting both ancient ⁵ and modern humans ^6–8. For instance, a recent Scottish study using whole-body MR angiography on low-med risk adults (n=1528, >40yrs old) found half had some artery narrowing (stenosis), a quarter in multiple vessels, with specific sites distributed throughout the body ^7,9. The early stages (e.g. fatty streaks) can start in childhood, as shown in US autopsy studies ¹⁰. However, prevalence is varied and notably low in some populations ^11–13. For instance, the lowest prevalence of coronary artery disease (CAD, based on CAC) was recently reported in the Tsimane ¹³ (i.e. forager-horticulturists of the Bolivian Amazon ¹⁴), despite their high inflammatory burden.

CVD is associated with many risk factors, which particularly implicate lifestyle ^1,2,15,16, while many related trials have improved and even reversed CVD (for reviews see ^17,18). For instance, a 2015 meta-analysis of 14 RCTs found that intensive lifestyle changes decreased coronary and carotid atherosclerotic burden ¹⁷. Indeed, since 1990 ¹⁹, several trials of diet/lifestyle changes have induced regression of CAD, as measured via coronary angiography ^19–26 (Table 1), while lowering symptoms and further cardiac events ^19,21–25 (except some cases of over-exercise ^19,20). In addition, many other trials on various populations (at risk of CVD) have induced regression of carotid atherosclerosis, as measured non-invasively via carotid artery thickening (which can correlate coronary disease ²⁷), with diet/lifestyle changes ^28–33 (Table 2) and even single extracts/nutrients ^34–41, providing further insight into mechanisms.

Reversal—how?

CAD regression trials generally used lipid-lowering diets (i.e. plant-based ^{19,21,22,24–26} or others ^20,23), either alone ^23,26, or with exercise ²⁰ and psychotherapies (i.e. stress reduction ^19,22 or yoga ^21,24,25). They lowered various other biomarkers, including weight/BMI ^{19,21,22,24–26}, insulin ²⁶, blood pressure ^21,24 and cholesterol ^19–26; some of which correlated regression (e.g. weight/TGs ²¹, blood pressure ²³ and LDL/HDL ^22,23). Similarly, carotid regression in various populations was achieved with various diets (i.e. Mediterranean ^30–33 (w/nuts ^30,31) and low calorie/carb/fat ^28,29,32,33), either alone ^30–33, or with exercise ²⁸ and psychotherapy ²⁹; as well as in blinded/placebo-controlled trials with specific extracts/nutrients (e.g. pomegranate juice ³⁴, plant oils ³⁵, omega-3 ³⁶, magnesium ³⁷, folate ³⁸, vit-B₁₂ ³⁹, carnitine ⁴⁰ and artichoke extract ⁴¹). These trials altered many related biomarkers, including weight ^{28,29,32,33,40,41}, blood pressure ^32–34, lipids ^{28,29,32,33,35–38,41}, immune ^28,35,37,38, glucose ^{28,29,32,37,38,41}, FMD/NO ^38–41, redox ^34,37 and homocysteine ^33,39; some of which correlated regression (e.g. blood pressure ³³, adiponectin/leptin ²⁹, TMAO ²⁸ and EPCs ³²). The following discussion will consider some underlying mechanisms in relation to diet, although they may be modulated by other aspects of lifestyle.

Interestingly, some CAD reports note rapid improvement in symptoms ^19,21,42 and heart perfusion ⁴³, suggesting improved vascular function and blood flow ¹¹. Of relevance, foods can acutely alter cardio-autonomic ⁴⁴ and vascular function ^45–47. For instance, in people with CAD/CHF, high fat meals can acutely suppress vasodilation (i.e. brachial artery at 4hrs ⁴⁵), while polyphenol-rich plant foods can boost vasodilation (e.g. at 1 ⁴⁶ and 2hrs ⁴⁷). These and other effects may involve redox modulation of vascular (e.g. endothelium, nitric oxide ¹¹), neuroendocrine (e.g. hypothalamus, sympathetic activity ^48,49) and heart tissues (e.g. cardiomyocytes ¹⁵, edema ⁴²). Another target is bone marrow-derived stem cells (e.g. Med diet ³² and exercise ⁵⁰), which can increase within 30 days (e.g. cocoa flavanols in CAD ⁵¹), and may support repair and function of the cardiovascular system.

Regarding atherosclerosis, regression characteristics will depend on population and intervention. The shortest trials tend to be those with extracts/nutrients, which have induced significant carotid regression at 3 months ^{34,35,38–40} (e.g. max: –19% with flax oil in obese elderly ³⁵), 6 months ^34,36,37,41 (e.g. max: –35% with artichoke extract in MetS ⁴¹) and 1 year ^34,39 (e.g. max: –35% with pomegranate juice in severe CAS ³⁴). Diet/lifestyle trials have induced carotid regression at 9 months to >1 year (e.g. max: –10% with Med diet + nuts in high CVD risk ³⁰), which has depended on baseline severity ³⁰ (e.g. cIMT ≥0.9mm ³¹) and dietary change (i.e. –12% with mod/high sat-fat reduction in obese adolescents ²⁹). Similarly, in CAD trials, coronary regression was most marked in the most severe lesions ^19,23,24, related to programme adherence ^19,21,22 (e.g. max: –18% with most adherence at 2yrs ²¹) and accompanied by improved stenosis geometry ⁵². Of further note, some additional case/clinical reports, using diet/lifestyle and drugs, even report reversal of extreme coronary stenosis (e.g. 90–95% obstruction) and heart failure (e.g. ejection fraction 25%) ^15,42,53,54, and extremely low recurrence of events (0.6%) ⁴³.

Regarding biological pathways, cholesterol is commonly implicated. In general populations (>40yrs old, no known CVD), LDL-c and non-HDL-c correlate the prevalence of subclinical atherosclerosis (e.g. peripheral ^6,7 and intracranial ⁸; LDL-c >60 mg/dl ⁶); while in CVD trials, intensive lipid-lowering with drugs (e.g. LDL-c <70/80 mg/dl) can induce regression of coronary, carotid and intracranial atherosclerosis ^55–58 (in relation to achieved LDL-c ⁵⁵ and HDL-c ^59,60). Similarly, diet/lifestyle trials reversing CAD also lowered LDL-c ^19–26, but varied HDL-c (e.g. –9.6% ²² to +5.6% ²¹) and TGs, with some reporting associations ^21–23 (and diet ²⁴). And of those inducing carotid regression, some altered cholesterol ^{29,36–38,41}, while some implicate other factors ^28,33,34,39 (see above). For instance, TMAO correlated carotid regression independent of traditional markers (e.g. cholesterol, insulin resistance and obesity) ²⁸. Drugs to control postprandial glucose have also induced some regression in diabetics (n=175 T2D, 1yr) ⁶¹. However, another controlled trial (n=349 T2D, 50% statins, 1yr) with nutritional ketosis did not induce carotid regression, despite favourably modulating many biomarkers (e.g. weight, BP, CRP, HbA1c, TGs, HDL-c, etc.), but also increasing LDL-c (i.e. 100 to 111 mg/dl) ⁶².

Plaque composition and development have been extensively studied (e.g. review). Briefly, progression involves ApoB lipoproteins (e.g. native or modified LDL ⁶³) and inflammation (e.g. M1 activity and foam cell expansion) ^63–67; while regression may involve essentially opposite pathways (e.g. HDL and M2 cells), allowing removal of damage/lipids and lesion/plaque shrinking ^68,69. These processes are affected by many factors. For instance, dietary sat-fat can increase LDL/HDL-c levels and oxidative/inflammatory modifications (e.g. vs low ⁷⁰ or unsat-fat ^71–74); whereas low fat, plant-based diets can decrease LDL-c and less so HDL-c, but may increase HDL anti-inflammatory activity (e.g. diet + exercise ⁷⁵). While HDL-c is inversely related to CVD, HDL function seems more important ^68,76 and related to other qualities (e.g. fluidity and redox) ^77–79. In particular, HDL plays a central role in reverse cholesterol transport (RCT; macrophage–liver), although may not always reflect the complete pathway (incl. liver–faeces) ⁸⁰. In general, HDL/RCT may be modulated by many factors (e.g. ↑: Med diet ⁷⁸, orange juice ⁸¹, flavonoids ⁸², olive oil ⁷⁷, omega-3s ^83,84, GSH ⁸⁵, fibre/SCFAs ^86,87; ↓: sat-fat ⁷⁴, immune/LPS ^83,88, oxidative stress ⁷⁹, FMO3/TMAO ⁸⁹). Dysregulation of lipid and lipoprotein metabolism is also related to hepatic insulin resistance ^74,90 and homocysteine ^91–95.

Plant-based?

The fact that CVD can be reversed with lifestyle, suggests it may not be an inevitable consequence of our genes or ageing, but environment. Further, while CVD may be accelerated by all kinds of contemporary risk factors (e.g. processed foods, inactivity, pollution, etc.), the fact that atherosclerosis was also prevalent in ancient populations (incl. hunter-gatherers) suggests an even more basic origin ⁵. Interestingly, compared to other great apes, we get more atherosclerosis and Alzheimer’s dementia ⁹⁶. So perhaps something lies within our divergence from great ape to ancient human?

The other great apes are largely plant-based, while our diet evolved to include more (vertebrate/meat-based) animal foods, with some putative benefits ⁹⁷. However, since plant-based diets appear to support reversal of CVD (see Tables 1/2 and cases ^{15,42,43,53,54}), perhaps there was also (delayed) compromise? Accordingly, while animal foods can support environmental adaptability and essential nutrition in the short-term, many have also been linked to CVD in the long-term, by various mechanisms (Table 3). For instance, we may have relatively high cholesterol levels compared to other mammals ^12,98, which correlate atherosclerosis (as above; and brain amyloid burden ^99,100), while plant-based diets typically lower our cholesterol. Further, the human species-specific loss of CMAH gene function (~2–3mya) may make us uniquely susceptible to Neu5Gc in red meat, which is present in human vascular tissues and plaques ¹⁰¹, and can promote inflammation and atherosclerosis ¹⁰². We also uniquely cook foods, where high/dry heat may especially increase the formation of cardiometabolic toxins in animal foods (e.g. AGEs) ¹⁰³.

On the other hand, some animal foods have more neutral or inverse associations; especially fish, in relation to long-chain omega-3s (i.e. EPA/DHA) ^36,104–107. However, some fish–health associations are U-curved (e.g. mortality in Western studies ¹⁰⁴) or offset by toxins (e.g. LDL ¹⁰⁸, T2D ¹⁰⁹ and CVD ¹⁰⁷). Fish oils are also prone to oxidation (e.g. supplements ¹¹⁰, gastric models ^111,112 and in vivo ^71,113,114), which may affect bioactivity ^115,116; although oxidation and Hg might be inhibited by polyphenol-rich plant foods ^111,112,117. Moreover, do they have benefits beyond ALA, the plant-based precursor? In trials, ALA (18:3) supplementation can increase blood EPA (20:5) and DPA (22:5), but not DHA (22:6) ¹¹⁸; although still might meet brain requirements ¹¹⁹. A 2014 review comparing ALA to EPA/DHA suggests they may have similar CVD benefits ¹²⁰, although optimal doses and contexts seem unclear. Also, a recent 2020 systematic review of 86 RCTs for CVD prevention found only slight benefits for both, partly offset by slightly increased prostate cancer ¹²¹; although confounding may include supplement quality and background diet ^105,110,122 (e.g. 2019 VITAL trial supp. data ¹²³).

Animal foods also supply vit-B₁₂, which is obviously essential ^124,125, and deficiency could undermine cardiovascular benefits of plant-based diets ¹²⁶. Note, incorporation of omega-3s into phospholipids is also related to (B₁₂-dependent) methylation, as discussed in a previous post. Nowadays B₁₂ is acquired mainly via meat and dairy (eggs = v low bioavailability) ¹²⁵; although B₁₂ is ultimately produced by microbes and various sources exist lower down the food chain (e.g. some plants/fungi ^124,125, insects ¹²⁷, molluscs and small fish). In studies with strict plant-based diets, B₁₂ is often supplemented ^15,19,43,54.

Most recently, our diet has evolved to include ultra-processed foods. Consequently, increased consumption of both animal and processed/refined plant foods are associated with risk of common diseases, including T2D and CVD ^128–132, while whole plant foods appear protective (paralleled by carb quality: GI/sugar vs fibre). Accordingly, several lifestyle interventions emphasised a whole food, plant-based approach ^21,22,24,25 (strictest: ^15,42,43). Note however, CAD regression was achieved despite an increase in TGs ¹⁹ related to simple carbs ²², while in another trial correlated lower TGs ²¹. Another aspect worth considering is fat quantity vs quality. Some CAD trials employed a very low 10% fat diet ^22,24,26,43, which may be difficult to follow ^20,21,23 (e.g. UK avg. ~35%). Is this necessary ¹³³? Greater CAD regression occurred with adherence to a lifestyle with 15% fat (no statins) ²¹, while recent case reports of CAD/CHF reversal had higher levels (e.g. ~19 ⁴² and 38% ¹³³), as did trials with carotid regression (e.g. 24% ²⁹) which even added fats (e.g. ~38 ³⁵ and 41% ³⁰). So perhaps fat quality is most important (e.g. low sat-fat ^29,133, high unsat-fat ^35,36 and whole food ^30,42,43).

Resources

• Dietary guidelines: WHO, Harvard, Countries (FAO)
• Plant-based: Ornish, NutritionFacts, PCRM, Plant-based UK

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