Statins may aggravate heart failure and atherosclerosis

Heart failure and atherosclerosis may be aggravated by the pervasive use of statin drugs through the depletion of coenzyme Q10 and ‘heme A’, which leads to a decrease in mitochondrial production of energy. Statins also suppress the biosynthesis of the antioxidant glutathione which serves to mitigate oxidative stress.
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Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms is the title of an article published in 2015 by a group of expert reviewers of clinical trials in the scientific journal Expert Review of Clinical Pharmacology. In this article, the authors revealed that “in contrast to the current belief that cholesterol reduction with statins decreases atherosclerosis, we present a perspective that statins may be causative in coronary artery calcification and can function as mitochondrial toxins that impair muscle function in the heart and blood vessels through the depletion of coenzyme Q10 […]. Statins inhibit the biosynthesis of selenium containing proteins, one of which is glutathione peroxidase serving to suppress peroxidative stress. An impairment of selenoprotein biosynthesis may be a factor in congestive heart failure, […]. Thus, the epidemic of heart failure and atherosclerosis that plagues the modern world may paradoxically be aggravated by the pervasive use of statin drugs.” ([i])

In a previous article titled Do cholesterol lowering Statins influence mortality rates ? Not really, I discussed a scientific study that was also published in 2015 in the British Medical Journal and which presented the findings of a team of researchers whose objective was “to determine whether there is a relation between statin utilisation and coronary heart disease (CHD) mortality in populations with different levels of coronary risk, and whether the relation changes over time.” ([ii]) They included data from 12 Western European countries ([iii) and found “a wide range of CHD mortality reduction between the years 2000 and 2012 (from 25.9% in Italy to 57.9% in Denmark) and statin utilisation increase (from 121% in Belgium to 1263% in Denmark).” However, they failed to establish a statistically significant relationship between cardiovascular mortality rates and what they described as “the large increase in statin utilisation.” In the countries studied, that increase “was not associated with CHD mortality, nor with its rate of change over the years.”

Matching both articles, it is not only clear that statins have no significant effect on CHD mortality, but that they may even aggravate the problem. The findings contradict what the medical profession has been and is still adamantly advocating. This erroneous belief in statins finds its origin in the first clinical trials that were performed in the 1990s. However, according to the authors of Statins stimulate atherosclerosis and heart failure, “after 2004–2005, all clinical trials, performed by scientists relatively free of conflict of interest with pharmaceutical industries, reported that statins were effective in lowering LDL-C[holesterol] but no significant beneficial effects were observed for the prevention of CHD. […] Our group did not adopt the results of industry-supported publications as reliable in our cholesterol guidelines. Thus, we are in a position not to accept the effectiveness of statins to prevent CHD, but rather we support the pharmacological interpretations that statins stimulate the development of atherosclerosis and heart failure. The lines of evidence described below led us to propose that current statin therapy should be critically and urgently reevaluated.”

Indeed, statins do lower cholesterol levels, but we should not forget that cholesterol plays an essential role in numerous vital functions. The integrity of the membranes of all body-cells is based mainly on a special type of fat called phospholipids and cholesterol. The cell’s membrane is like a film made up of revolving doors that control what goes in and out of the cell. Cholesterol forms a key element in that system of revolving doors. A very small amount of the body’s cholesterol is used by the adrenal glands to form certain hormones. Cholesterol-based hormones are progesterone and estrogen (formed in the ovaries) and testosterone (formed in the testes). These glands can also synthesize their own cholesterol. As explained by Dr. Masquelier, the problem is not the cholesterol, but its oxidized forms. Therefore, “any substance that prevents what is called lipoprotein [cholesterol] oxidation will reduce this danger of plaque formation [atherosclerosis].”

Plaque formation, also known as atherosclerosis, begins because the vascular wall does not recognize the LDL it has been oxidized, deformed, and wrecked by free radicals. Plaque formation, according to Dr. Masquelier, begins when the LDL is wrecked and its “cargo” turns rancid due to oxidative stress. In response to these events, the vascular wall actively attempts to neutralize what it no longer recognizes as safe and beneficial. In fact, the reaction of the vascular wall is the normal inflammatory response of any tissue that is confronted by what it perceives as a foreign invader. Normal LDL-cholesterol is not an invader. To the contrary, it is welcomed by the cells. But, the wrecked LDL must be kept from circulating throught the body. It must be neutralized. And this process, by way of which the vascular wall absorbs the oxidized cholesterol to keep it from freely flowing around, forms the onset of atherosclerotic plaque and cardiovascular disease. Masquelier’s OPCs interfere with this process by protecting LDL-cholesterol against oxidation.

Now, let’s see how statins may aggravate coronary heart disease instead of mitigating it. The authors of Statins stimulate atherosclerosis and heart failure begin by pointing out that “the mechanism for the impairment in heart muscle function appears to be related to impaired mitochondrial function, which in turn is related to statin depletion of [the vitamin-like co-enzyme] CoQ10, selenoproteins [such as glutathion peroxidase / GPx] and ‘heme A’ [a precursor of hemoglobin which facilitates oxygen transport], all required for normal mitochondrial function.” The mitochondria are subcellular units that produce energy by “burning” fatty acids and sugars. This “burning” consists of a chain of events wherein Coenzym Q10, GPx and heme A play an essential role. Quite logically, reduced levels of these compounds impair the functioning of muscle cells, which is of particular importance in cells with exceedingly high demands for energy, such as cardiac muscle cells. “Thus,” according to the researchers, “statins are mitochondrial toxins” or “general cell toxins,” also because the form of CoQ10 called ubiquinol “is recognized to be a clinically relevant antioxidant in different cellular compartments, especially the mitochondrial membranes, where it protects mitochondrial DNA from damage.”

The expert reviewers continue by stating that “statin-induced impairment in heart muscle function appears to be permanent, and even though patients may clinically benefit from discontinuation of the statin along with supplemental CoQ10, we believe that many years of statin drug therapy result in the gradual accumulation of mitochondrial DNA damage. A prolonged decrease in mitochondrial CoQ10 would diminish the ability to protect mitochondrial DNA from free radical damage. After a critical percentage of mitochondrial DNA is mutated, offspring mitochondria will progressively lose their efficiency to produce [energy] and simultaneously can generate more free radicals and result in a self-perpetuating vicious cycle. The negative consequences of statin-induced increase in coronary artery disease, coupled with a direct statin toxicity upon the [heart muscle], can be expected to be additive with enormous clinical implications. With more than one million heart failure hospitalizations every year in the USA, the rapidly increasing prevalence of congestive heart failure is now described as an epidemic and it is likely that statin drug therapy is a major contributing factor.”

Nature has endowed the human body with antioxidative enzymes that neutralize the “sparks” (free radicals) that may be produced when we “burn” fatty acids and sugars. Statins not only interfere with the synthesis of glutathion peroxidase, which is one of these antioxidative enzymes, but they also lower the levels of similar innate enzymes, such as superoxide dismutase (SOD) and catalase. So, when the free radical scavenging enzymes are depleted, our cells and tissues become more exposed to the “sparks” that cause oxidative damage. In turn this may also increase the risk of CHD. In Statins stimulate atherosclerosis and heart failure the reviewers described how, “in accordance with the mechanisms described above, glutathione peroxidase activity in [red blood cells] was shown clinically to be inversely associated with CHD events and positively with event-free survival when patients with CHD were followed up for 5.4 years.” Other than this, patients using statins should be informed of all of statins’ adverse effects, including the onset of diabetes mellitus, carcinogenicity, teratogenicity and central and peripheral nervous disorders besides the wellknown skeletal muscle breakdown and liver injury.

When I once put this question to Professor Masquelier, he replied: “Yes, you're right. You see, it’s vital that there is cholesterol in all cells, absolutely essential. The problem is not being able to eliminate it when it can no longer be used, when it has been oxidized, […].” Besides this, lowering cholesterol intake is useless to begin with because roughly 1.5 g of cholesterol is required daily in adults for a variety of essential functions and only a small fraction of this amount is ingested with food. For instance, 0.3 g (about half of ingested cholesterol) can be obtained from 2 eggs plus 100 g meat and the rest (1.2 g), the majority of daily required amount, is produced by the human body itself. In response to lowering cholesterol intake, the body will simply produce more of it. What should we then do to prevent heart attacks ? Well, Masquelier explained that “any substance that prevents what is called lipoprotein [LDL] oxidation will reduce this danger of plaque formation. We can prevent heart attacks thanks to antioxidative substances and OPCs are the type of substance that may prevent LDL [cholesterol] from becoming oxidized. It wasn’t until the 1970s till we knew exactly how it happened. For several years, we could see this mechanism there, but only in the laboratory. We conducted experiments with OPCs on human LDL and we saw that the oxidation rate was certainly decreasing. We learned that by inhibiting the oxidation of LDL, which is the first carrier of cholesterol, we can protect the vascular wall against a build-up of artherosclerotic plaque.” Let me add that taking a CoQ10 supplement in addition to Masquelier’s OPCs doesn’t seem to be a bad idea either.

[I] Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms; Harumi Okuyama, Peter H Langsjoen, Tomohito Hamazaki, Yoichi Ogushi, Rokuro Hama, Tetsuyuki Kobayashi & Hajime Uchino; Expert Review of Clinical Pharmacology, 8:2, 189-199 (2015). DOI: 10.1586/17512433.2015.1011125. 
[ii] Time trends in statin utilisation and coronary mortality in Western European countries; Federico Vancheri, Lars Backlund, Lars-Erik Strender, Brian Godman, Björn Wettermark; Published by the British Medical Journal Publishing Group Limited; 2015.
[iii] Finland, Scotland, Germany, Sweden, Norway, Denmark, the Netherlands, Italy, Belgium, Spain, Portugal and France.