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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