Eliminating atherosclerotic cardiovascular disease residual risk

Abstract

Daniel Steinberg, one of the founders of lipidology and preventive cardiology, noted: We know that intervention in middle-aged men and women reduces LDL (low-density lipoprotein) levels by 25%–30% and that in a 5- or 6-year trial this reduces hard endpoints of coronary heart disease (CHD) risk by about 30%. Now, the optimist looks at these results and declares a therapeutic triumph; the pessimist looks at the same results and asks, ‘Why aren’t we preventing the other 70% of events?1 Seventy percent of residual risk is unacceptable, because atherosclerosis can be completely prevented in nearly every case if treated early enough and aggressively enough. ‘Residual risk’ is a euphemism for failure to prevent. Myocardial infarctions are potentially 95% preventable; most other sequelae of atherosclerosis are nearly as preventable. Failure should be rare. There is compelling evidence that atherosclerosis occurs only when LDL particles enter the intimal space, which initiates the inflammatory cascade that is atherosclerosis. If there are no LDL particles in the intima, atherogenesis does not occur.2 This requires keeping circulating LDL-cholesterol (LDL-C) levels low enough (the lower, the better), decreasing them early enough (the earlier, the better), and maintaining them throughout one’s lifetime (the longer, the better), which early detection and modern treatments can readily achieve in nearly every case.3 In 2023, with the available therapies, we might hypothetically say that lipid disorders should be a disease rarely inadequately treated. LDL-cholesterol reduction is a primary goal for reducing the risk of atherosclerotic cardiovascular disease: lower is better for lifetime, earlier is better, and lowest is best. LDL-cholesterol is a driving force for broad spectrum, progressive pathophysiology and multiple disease states adversely impacting longevity and quality of life. *Central graph from the paper by Cybulska B, et al. Prog Cardiovasc Dis. 2021; 67:65–74. doi: 10.1016/j.pcad.2020.12.008 (with permission, licence No. 5574150482892). Many facts suggest that a desirable, physiologic level of LDL cholesterol is far lower than previously assumed:2 Serum LDL-C in utero and in newborns averages 20–40 mg/dL (0.52–1.03 mmol/L). During gestation and after birth, humans are forming new cells at prodigious rates yet require little contribution of cholesterol from LDL. All cells of the body make their own cholesterol (plus a small portion derived from HDL-C). Those born with complete absence of proprotein convertase subtilisin kexin type 9 (PSCK9; loss of function mutation) suffer no ill consequences from lifelong near zero circulating LDL-C and have no atherosclerosis. Brown and Goldstein showed that fibroblast receptors for LDL are maximized at a concentration of 25 mg/dL (0.67 mmol/L) due to feedback control. Excess cholesterol beyond that is taken up either by hepatocytes or scavenger receptors on intimal macrophages that have no feedback control and thus accumulate much larger amounts of cholesterol. Randomized controlled trials (RCTs) and Mendelian randomization analyses demonstrate that there is log-linear relationship between atherosclerotic cardiovascular disease (ASCVD) and LDL-C at the highest levels down to near zero. The hazard ratio of 1.0 (meaning no excess risk) is achieved at an LDL-C of approximately 38 mg/dL (0.98 mmol/L). Many RCTs show that lowering LDL-C at any stage is beneficial, but doing so as early as possible is far better. Elevations in mid-life LDL-C also correlate with increased risk for neurologic disease, especially vascular and Alzheimer’s dementia, as well as Parkinson’s disease. Considering this, the most desirable LDL-C appears to be that of the newborn, 20–40 mg/dL (0.52–1.03 mmol/L). Such a low level is likely not needed if LDL-C is well below 70 mg/dL (1.81 mmol/L) from birth, remains at that level through life and all other risk factors (hypertension, hyperglycaemia, obesity, inflammation, lipoprotein(a), and many others) are absent or well controlled. That is not common, but treatment can achieve it when needed.2 Unfortunately, most people are not entirely free from other risk factors. Even living as healthfully as possible in an industrialized society still means exposure to a broad spectrum of chemicals and other pollutants, high stress, difficulty maintaining a healthy lifestyle, and much else. Indigenous people who live in a natural habitat far from industrialized areas, such as the Tsimane people of Bolivia, and all other mammals have very low cholesterol4 and no atherosclerosis.2 Equally important is intervention at the very earliest opportunity. Patients with complete absence of PCSK9, with LDL-C levels under 20 mg/dL (0.52 mmol/L) from birth, are on track to live event-free for one hundred years or beyond per the calculations of Horton et al.5 (assuming other major risk factors are well controlled). The risk of atherosclerosis is often estimated by the annualized burden of LDL-C times the number of years arteries are exposed to it.2 That is why the cholesterol-years calculation has been introduced, indicating the level over which the risk of the first/recurrent ASCVD event is the highest. Delay in treatment is hazardous. As Brown and Goldstein6 noted, ‘the earliest symptom is often sudden death’. Atherosclerosis begins in early childhood, even in utero in some, and progresses over time unless action is taken to halt it.7 Virtually everyone living in industrialized societies develops atherosclerosis. The earlier the process of LDL-C ‘invading’ the intima is halted, the less atherosclerosis will occur and the easier it will be to treat. Current practice tends to delay treatment until after a cardiovascular event or patients are much older and at unusually high risk. Delaying treatment until an event has already occurred (if the patient has survived it) means missing the opportunity to inhibit plaque formation and prevent both acute events and long-term consequences. Physicians do not forestall treatment of hypertension, diabetes, rheumatoid arthritis, infections, and many other diseases until major damage has occurred. Why is dyslipidaemia so often ignored? Keeping LDL-C below 55–70 mg/dL (1.40–1.81 mmol/L; depending on the risk) from as early in life as possible, or even lower if other risk factors are present, seems very likely to eliminate most adverse consequences of atherosclerosis. If treatment is not begun until mid-life or later, if plaque is already present or if there are other significant risk-enhancing factors, then even lower LDL-C is a better goal. This was one of the reasons for defining the extremely high CVD risk group, for which a recommended level of LDL-C is <40 mg/dL (1.03 mmol/L).8 Lifestyle improvement, while invaluable, has too low of a success rate to obviate the need for medications in most patients. It is important to view LDL particles as a vascular toxin. LDL is the end product of lipoprotein metabolism and is a type of biochemical waste. If not cleared by hepatocytes, it is rendered toxic by oxidative modification in the subendothelial space. Greater elimination of a toxin yields lower toxicity and lower risk of disease. LDL particles are a notable example of this. Fortunately, the lipid-lowering medications are among the safest in use, are highly cost effective, easy to use, and very efficacious. There seem to be no significant adverse problems from LDL no matter how low it gets. Recent randomized studies and meta-analyses have also shown that even very low LDL-C (<25 mg/dL, < 0.67 mmol/L) does not increase risk for dementia or haemorrhagic stroke.2,9 Atherosclerosis is the major cause of or contributor to stroke, dementia, heart and kidney failure, peripheral arterial disease, mesenteric and renal artery disease, erectile dysfunction, aortic disease and aneurysm, frailty, and poor aging and more (Figure 1). Preventing these diseases is rarely mentioned as a goal of treatment, but obviously should be. Atherosclerosis is also the greatest cause of disease, disability, and death in the USA and globally. Yet, most physicians do not act as if it were the highest priority for their patients. Many cases go untreated. When treatment is finally begun, it is almost always only when a patient is much older with more advanced disease, is usually inadequate, and many patients are just advised to watch their diet and return in a year. It is unfortunate that only 2/10 individuals know their cholesterol level, a much lower number in comparison to blood pressure or glucose level awareness. Algorithms and risk calculators have failure rates as high as 50%.2 They also perform poorly in the evaluation of risk in young individuals. Aging clocks such as the inflammatory clock of aging and epigenetic aging clocks can provide information on cardiovascular aging (vascular stiffness, adverse cardiac remodelling, and endothelial senescence) but are not yet ready for widespread application. We suggest that instead it is best to individualize care for each patient, assessing family history, the degree of disease, and length of exposure to all risk factors. We have powerful tools to reduce the residual failure rate to near zero in all patients willing to comply, something today we are far from. Atherosclerosis is the most preventable chronic disease, yet it remains the greatest killer of people worldwide, a painful paradox. It is time to assess cardiovascular risk factor burden from childhood on, to treat risk factors more expeditiously and intensively, and to prevent atherosclerotic plaque formation as early as possible. As Brown and Goldstein said, ‘Early intervention may well put an end to the epidemic of coronary heart disease that ravaged Western populations in the 20th century’.10 Then half of deaths were from infarctions. We have done better since—but it is still far too many. The goal should be to make atherosclerosis a rare disease. We have the means to do so; should it not be our top priority? M.E.M.: none; M.B.: speakers bureau: Amgen, Daiichi Sankyo, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Pfizer, Sanofi-Aventis, Teva, and Zentiva; consultant to Adamed, Amgen, Daiichi Sankyo, Esperion, NewAmsterdam, Novartis, Novo-Nordisk, and Sanofi-Aventis; grants from Amgen, Daiichi Sankyo, Mylan/Viatris, Sanofi, and Valeant; P.P.T.: speakers bureau for Amgen and consultant to Novartis.

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