{"product_id":"the-changing-landscape-of-atherosclerosis-what-every-patient-should-know","title":"The Changing Landscape of Atherosclerosis: What Every Patient Should Know","description":"\u003cp\u003eAtherosclerosis—the silent buildup of fatty plaque inside artery walls—has undergone a dramatic transformation in recent decades. Once considered a disease of middle-aged Western men, it now contributes to the majority of deaths worldwide, striking younger people, more women, and individuals from diverse ethnic backgrounds than ever before. This comprehensive review by Dr. Peter Libby of Brigham and Women's Hospital and Harvard Medical School examines how shifting risk factors, newly recognized inflammatory pathways, and even bone marrow mutations are reshaping our understanding of the disease. The findings point to exciting new treatment opportunities, including therapies that target inflammation directly and offer hope even for patients whose cholesterol is already well controlled.\u003c\/p\u003e\n\n\u003ch1\u003eThe Changing Landscape of Atherosclerosis: What Every Patient Should Know\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Understanding Atherosclerosis and Why It Matters\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#changing-face\"\u003eThe Changing Face of Atherosclerosis: Who Gets It Now?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#lipid-risk\"\u003eReassessing Cholesterol: From LDL to Triglycerides and Lipoprotein(a)\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#inflammation\"\u003eInflammation: The Hidden Driver of Atherosclerosis\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#mechanisms\"\u003eInside the Artery Wall: How Plaques Form and Progress\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#bone-marrow\"\u003eThe Bone Marrow Connection: Clonal Haematopoiesis\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eClinical Implications: What This Means for Treatment\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations: What We Still Don't Know\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations for Patients\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eAtherosclerosis now causes most deaths worldwide, affecting more younger women, minorities, and developing countries than before.\u003c\/li\u003e\n\u003cli\u003eLDL, triglyceride-rich lipoproteins, and lipoprotein(a) all cause atherosclerosis; inflammation is a proven driver of heart attacks and strokes.\u003c\/li\u003e\n\u003cli\u003eClinical trials CANTOS, COLCOT, and LoDoCo2 showed anti-inflammatory drugs reduce recurrent events even with controlled cholesterol.\u003c\/li\u003e\n\u003cli\u003eClonal haematopoiesis, age-related bone marrow mutations, is a common and potent cardiovascular risk factor in people over 70.\u003c\/li\u003e\n\u003cli\u003eKnow LDL, triglycerides, and hsCRP; manage abdominal weight, sleep, and sugary drinks; lifestyle reduces risk at every genetic level.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Understanding Atherosclerosis and Why It Matters\u003c\/h2\u003e\n\n\u003cp\u003eAtherosclerosis is the disease process in which cholesterol, fat, and inflammatory cells accumulate inside the walls of arteries, forming plaques that can narrow blood vessels or rupture and trigger blood clots. It is the underlying cause of several life-altering conditions: \u003cstrong\u003emyocardial infarction\u003c\/strong\u003e (heart attack), \u003cstrong\u003eischaemic cardiomyopathy\u003c\/strong\u003e (weakened heart muscle from reduced blood flow, the most common cause of heart failure), \u003cstrong\u003estrokes\u003c\/strong\u003e (which can rob people of independence, mobility, cognition, or the ability to communicate), and \u003cstrong\u003eperipheral arterial disease\u003c\/strong\u003e (which limits activity and can jeopardize limbs).\u003c\/p\u003e\n\n\u003cp\u003eFor decades, atherosclerosis was viewed primarily as a problem of industrialized, wealthy nations. But the world has witnessed an \"epidemiological transition\": improved sanitation, vaccination, and treatment of acute infections have dramatically reduced deaths from communicable diseases in developing countries. As a result, more people now survive long enough to develop chronic diseases like atherosclerosis.\u003c\/p\u003e\n\n\u003cp\u003eThis transition has created a phenomenon called \u003cstrong\u003e\"morbidity extension\"\u003c\/strong\u003e in the developing world. Many individuals escape early death from infection, but they must bear the burden of chronic cardiovascular disease alongside arthritis, depression, and other long-term health impediments. \u003cstrong\u003eToday, the major pool of risk for developing cardiovascular disease is no longer in Western countries but in the more populous developing world\u003c\/strong\u003e, and atherosclerotic cardiovascular disease now accounts for the majority of deaths worldwide.\u003c\/p\u003e\n\n\u003cp\u003eThe numbers are stark. According to the Global Burden of Disease study, the worldwide prevalence of ischaemic heart disease has risen from about \u003cstrong\u003e100 million cases in 1990 to over 180 million cases in 2019\u003c\/strong\u003e. Perhaps even more concerning, in some regions of the United States and the United Kingdom, the decline in heart disease prevalence that had been attributed to successful risk-factor control has \u003cstrong\u003eslowed or even halted between 2014 and 2019\u003c\/strong\u003e. We may be losing ground in prevention even in high-income countries.\u003c\/p\u003e\n\n\u003ch2 id=\"changing-face\"\u003eThe Changing Face of Atherosclerosis: Who Gets It Now?\u003c\/h2\u003e\n\n\u003cp\u003eThe classic picture of a heart attack candidate was a middle-aged white man with high blood pressure, high cholesterol, and a cigarette habit. That image has evolved considerably. While individuals in mid-life still face risk, coronary artery disease now affects an increasing number of \u003cstrong\u003eyounger women\u003c\/strong\u003e, and—as populations age—the \u003cstrong\u003every old\u003c\/strong\u003e now account for a growing proportion of cardiac patients.\u003c\/p\u003e\n\n\u003cp\u003eSeveral positive trends are worth celebrating: effective treatments for high blood pressure and lipid disorders have improved control of hypertension and hypercholesterolemia, and reductions in smoking (along with decreased second-hand smoke exposure) have gained a foothold in many societies. However, new challenges have emerged to replace the old ones.\u003c\/p\u003e\n\n\u003ch3\u003eThe Obesity Epidemic and Metabolic Syndrome\u003c\/h3\u003e\n\n\u003cp\u003eAn epidemic of obesity has swept across the world. Excess body fat, especially fat accumulated in the abdomen, and fatty liver drive \u003cstrong\u003einsulin resistance\u003c\/strong\u003e, which sets the stage for diabetes and links closely with hypertension. This cluster of conditions—collectively known as the \u003cstrong\u003emetabolic syndrome\u003c\/strong\u003e—includes increased waist circumference, low HDL (protective) cholesterol, high blood pressure, and elevated fasting blood glucose.\u003c\/p\u003e\n\n\u003cp\u003eThe prevalence of the metabolic syndrome in the United States \u003cstrong\u003erose by 35% from 1988–1994 to 2007–2012\u003c\/strong\u003e. Women, members of minoritized groups, and populations in developing countries now bear an increasing burden of atherosclerotic cardiovascular disease.\u003c\/p\u003e\n\n\u003cp\u003eThere are important ethnic differences in how the body handles excess fat. \u003cstrong\u003eAsian and South Asian individuals\u003c\/strong\u003e, as well as people of some ethnicities in Central and South America, can develop metabolic problems—including glucose intolerance—at lower abdominal girths than white individuals. Given the large populations in Asia, Central and South America, increased prosperity with shifts away from traditional diets, continuing tobacco use, and the growing burden of obesity and diabetes present an enormous public health challenge.\u003c\/p\u003e\n\n\u003ch3\u003eAir Pollution, Diet, and Other Modern Exposures\u003c\/h3\u003e\n\n\u003cp\u003eBeyond obesity and insulin resistance, researchers are investigating additional environmental contributors: \u003cstrong\u003eair pollution, environmental noise, transitions from traditional diets to less healthy ones, and impaired sleep\u003c\/strong\u003e may all be mitigating some of the advances made in prevention. Among the most readily remedied dietary shifts, the consumption of \u003cstrong\u003esugar-sweetened beverages, often high in fructose\u003c\/strong\u003e, may contribute to obesity and its adverse metabolic consequences. Modifiable risk factors contribute enormously to the global burden of ischaemic heart disease.\u003c\/p\u003e\n\n\u003ch2 id=\"lipid-risk\"\u003eReassessing Cholesterol: From LDL to Triglycerides and Lipoprotein(a)\u003c\/h2\u003e\n\n\u003ch3\u003eLDL: Still the Prime Suspect\u003c\/h3\u003e\n\n\u003cp\u003e\u003cstrong\u003eLow-density lipoprotein (LDL) cholesterol\u003c\/strong\u003e—the \"bad\" cholesterol—is encircled by its signature protein component, apolipoprotein B, and it definitively causes atherosclerosis. Scientists note that if the entire population maintained LDL concentrations similar to those of a newborn baby (or of most adult animals), \u003cstrong\u003eatherosclerosis might well become an orphan disease\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eThe duration and extent of exposure to above-ideal LDL concentrations matters enormously. Lifelong elevated LDL levels have already sown the seeds of atherosclerosis in millions of people, increasing their lifetime risk of cardiovascular disease. Treating children and adolescents with cholesterol-lowering drugs, however, presents many challenges.\u003c\/p\u003e\n\n\u003cp\u003eEven with effective treatments for LDL, blood pressure, and other traditional risk factors, a \u003cstrong\u003econsiderable residual risk\u003c\/strong\u003e for cardiovascular events remains. Recent clinical trials of novel heart medications, conducted in patients already receiving optimal standard therapy, found that \u003cstrong\u003eabout 1 in 20 patients will have a recurrent ischaemic event in the year after an acute coronary syndrome\u003c\/strong\u003e. In the United States, \u003cstrong\u003e1 in 10 individuals who survive an acute heart attack will require readmission to the hospital within one month\u003c\/strong\u003e—at considerable personal and societal cost.\u003c\/p\u003e\n\n\u003ch3\u003eThe HDL Story: A Paradigm Shift\u003c\/h3\u003e\n\n\u003cp\u003eFor decades, doctors believed that \u003cstrong\u003ehigh-density lipoprotein (HDL)\u003c\/strong\u003e—the \"good\" cholesterol—protected against atherosclerosis. That belief has been seriously challenged. Recent human genetic studies, along with the failure of several independent drug trials that raised HDL levels without reducing heart events, have \u003cstrong\u003ecalled into question HDL's protective effect\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eHowever, the story is not entirely closed. \u003cstrong\u003eMendelian randomization studies\u003c\/strong\u003e (which use genetic variations to infer cause-and-effect relationships) that corrected for \"pleiotropy\" (one gene influencing multiple traits) have provided some support for HDL's protective role. Moreover, the \u003cem\u003efunction\u003c\/em\u003e of HDL particles—such as their capacity to remove cholesterol from cells (a process called \u003cstrong\u003echolesterol efflux\u003c\/strong\u003e) or their anti-inflammatory actions—may still protect against atherosclerosis, even if the simple measurement of total HDL cholesterol level does not tell the whole story.\u003c\/p\u003e\n\n\u003ch3\u003eThe Rise of Triglyceride-Rich Lipoproteins (TGRL)\u003c\/h3\u003e\n\n\u003cp\u003eFor many years, plasma triglyceride levels were overlooked as a risk factor. The belief in HDL's protective effect led researchers to \"adjust\" triglycerides for HDL, which attenuated the risk attributed to triglyceride-rich lipoproteins (TGRL). That approach was a mistake.\u003c\/p\u003e\n\n\u003cp\u003eA recent ranking of lipid risk factors has \u003cstrong\u003edemoted HDL as a protective factor and identified TGRL as a potent predictor of cardiovascular risk\u003c\/strong\u003e. Unlike HDL, contemporary human genetic studies strongly support a causal role for TGRL in atherosclerosis and its complications.\u003c\/p\u003e\n\n\u003cp\u003eHere is how the biology works: a crucial enzyme called \u003cstrong\u003elipoprotein lipase\u003c\/strong\u003e normally breaks down triglycerides in TGRL particles. Several proteins regulate this enzyme:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eApolipoprotein CIII\u003c\/strong\u003e, \u003cstrong\u003eANGPTL3\u003c\/strong\u003e, and \u003cstrong\u003eANGPTL4\u003c\/strong\u003e inhibit lipoprotein lipase, causing TGRL particles to accumulate.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eApolipoprotein V\u003c\/strong\u003e augments lipoprotein lipase activity and enhances TGRL clearance.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003ePeople who inherit genetic variants that raise TGRL experience more atherosclerotic events, while those with variants that lower TGRL have better outcomes. Interestingly, the triglyceride component itself does not appear to be what makes TGRL dangerous. Like LDL, TGRL particles carry apolipoprotein B and contain cholesterol, which they can deliver directly to macrophages (scavenger cells) inside artery plaques. TGRL also provoke inflammation, in part because of their apolipoprotein CIII content. In fact, \u003cstrong\u003eTGRL concentrations correlate with inflammatory status better than LDL itself does\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eThis refocusing on TGRL as a causal risk factor—combined with the disappointing results of HDL-raising therapies—has significant treatment implications that we will explore later.\u003c\/p\u003e\n\n\u003ch3\u003eLipoprotein(a): A Genetic Risk Factor You Can't Change with Diet\u003c\/h3\u003e\n\n\u003cp\u003eAnother important player is \u003cstrong\u003elipoprotein(a)\u003c\/strong\u003e, a special form of LDL that has long been associated with atherothrombotic (plaque + clot) risk. Lipoprotein(a) consists of an LDL particle whose apolipoprotein B has bound covalently to a second protein called apolipoprotein(a). This particle carries oxidized lipids and may inhibit the body's ability to break down blood clots, because it structurally resembles plasminogen (a key clot-dissolving protein).\u003c\/p\u003e\n\n\u003cp\u003eConcordant human genetic studies provide persuasive evidence that elevated lipoprotein(a) is not just associated with, but actually \u003cstrong\u003ecauses\u003c\/strong\u003e, both atherosclerosis and \u003cstrong\u003ecalcific aortic valve disease\u003c\/strong\u003e. This is a genetic risk factor that patients cannot modify through diet or exercise—though targeted therapies are in development.\u003c\/p\u003e\n\n\u003ch2 id=\"inflammation\"\u003eInflammation: The Hidden Driver of Atherosclerosis\u003c\/h2\u003e\n\n\u003cp\u003eBeyond abnormal cholesterol levels, a convincing body of experimental and clinical evidence now shows that \u003cstrong\u003einflammation participates fundamentally in atherosclerosis and the triggering of heart attacks and strokes\u003c\/strong\u003e. Importantly, inflammation does not replace or minimize the role of lipids; rather, inflammatory responses are the pathways that \u003cem\u003elink\u003c\/em\u003e lipids and other traditional risk factors to the disease. For example, remnant lipoprotein levels show links with C-reactive protein (CRP), a biomarker of inflammation, and substantial evidence implicates inflammation in high blood pressure.\u003c\/p\u003e\n\n\u003ch3\u003eThe Immune System's Dual Role\u003c\/h3\u003e\n\n\u003cp\u003eThe immune system plays a complex and often contradictory role in atherosclerosis. Both branches of immunity are involved:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eInnate immunity\u003c\/strong\u003e (the older, non-specific arm of the immune system) relies largely on cytokines (chemical messengers) and macrophages (scavenger cells). A simple blood test for \u003cstrong\u003ehigh-sensitivity C-reactive protein (hsCRP)\u003c\/strong\u003e can measure overall innate immune activity and is a validated, clinically useful gauge of atherosclerotic risk—even independently of all traditional risk factors.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAdaptive immunity\u003c\/strong\u003e (the targeted, memory-based arm) involves T lymphocytes and B lymphocytes. T-helper 1 (Th1) cells generally \u003cem\u003eaggravate\u003c\/em\u003e atherosclerosis, while T-helper 2 (Th2) and regulatory T cells (Tregs) can \u003cem\u003emute\u003c\/em\u003e the process. B1 cells produce natural IgM antibodies that \u003cem\u003emitigate\u003c\/em\u003e experimental atherosclerosis, while B2 cells can produce antibodies that drive the disease. One candidate target identified from mouse studies is the mitochondrial enzyme \u003cstrong\u003eALDH4A1\u003c\/strong\u003e.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch3\u003eMetabolic Connections\u003c\/h3\u003e\n\n\u003cp\u003eNew links between inflammation, immunity, and metabolism have recently emerged. Inflammatory activation of immune cells and endothelial cells shifts their metabolism toward \u003cstrong\u003eglycolysis\u003c\/strong\u003e (sugar-burning). Altered \u003cstrong\u003etryptophan metabolism\u003c\/strong\u003e has also drawn attention: cytokines induce an enzyme called indolamine dioxygenase, which breaks down tryptophan and increases production of kynurenine and its metabolites. This pathway may actually serve a counter-regulatory function by dampening inflammation and the cellular immune response.\u003c\/p\u003e\n\n\u003ch3\u003eProof from Clinical Trials: CANTOS, COLCOT, and LoDoCo2\u003c\/h3\u003e\n\n\u003cp\u003eThe most dramatic validation of the inflammation theory came from large clinical trials showing that \u003cstrong\u003etargeting inflammation can reduce cardiovascular events\u003c\/strong\u003e—even in patients already receiving optimal cholesterol-lowering and blood-pressure-lowering therapy.\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eThe CANTOS trial\u003c\/strong\u003e (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) tested canakinumab, an antibody that neutralizes the proinflammatory cytokine IL-1β, in patients with stable coronary artery disease who had experienced a heart attack at least one month earlier. Participants had evidence of ongoing inflammation (hsCRP above 2 mg\/L) despite standard medical therapy, and their baseline LDL was approximately 2 mM (81 mg\/dL)—already quite well controlled.\u003c\/p\u003e\n\n\u003cp\u003eResults of CANTOS:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e15% relative reduction\u003c\/strong\u003e in the risk of recurrent heart attack, stroke, or cardiac death with anti-inflammatory therapy.\u003c\/li\u003e\n  \u003cli\u003eIn an \"on-treatment\" analysis, patients who responded with a greater-than-median reduction in hsCRP had a \u003cstrong\u003e26% reduction\u003c\/strong\u003e in the primary endpoint and a decrease in all-cause mortality.\u003c\/li\u003e\n  \u003cli\u003eBecause IL-1β helps fight infections, there was a small but statistically significant increase in infections (including fatal infections) in patients receiving canakinumab.\u003c\/li\u003e\n  \u003cli\u003eExploratory analyses found a highly significant reduction in incident and fatal lung cancer, which counterbalanced the infection risk.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eThe COLCOT trial\u003c\/strong\u003e (Colchicine Cardiovascular Outcomes Trial) tested colchicine—a natural plant-derived anti-inflammatory medication long used for gout and pericarditis—in patients treated early (within 4–30 days) after an acute coronary syndrome. The results:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003e23% reduction\u003c\/strong\u003e in the composite primary endpoint, driven primarily by fewer revascularization procedures (procedures to restore blood flow).\u003c\/li\u003e\n  \u003cli\u003eThe incidence of pneumonia \u003cstrong\u003emore than doubled\u003c\/strong\u003e in the colchicine-treated group.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003e\u003cstrong\u003eThe LoDoCo2 study\u003c\/strong\u003e (Low Dose Colchicine 2) confirmed the efficacy of low-dose colchicine in reducing recurrent cardiovascular events after acute coronary syndromes.\u003c\/p\u003e\n\n\u003cp\u003eHowever, not all anti-inflammatory interventions have succeeded. A trial of \u003cstrong\u003elow-dose weekly methotrexate\u003c\/strong\u003e—a common anti-inflammatory drug—did not improve cardiovascular outcomes, nor did it meaningfully reduce inflammation in the population studied.\u003c\/p\u003e\n\n\u003ch3\u003eObesity, Environment, and Inflammation\u003c\/h3\u003e\n\n\u003cp\u003eAdipose (fat) tissue is not inert—it abounds with inflammatory cells and produces proinflammatory mediators. Inflammation mechanistically links obesity, insulin resistance, and atherosclerotic risk. Environmental factors including \u003cstrong\u003eair pollution, noise, disturbed sleep, and other stressors\u003c\/strong\u003e also appear to increase cardiovascular risk, at least in part by activating inflammatory pathways.\u003c\/p\u003e\n\n\u003ch2 id=\"mechanisms\"\u003eInside the Artery Wall: How Plaques Form and Progress\u003c\/h2\u003e\n\n\u003cp\u003eUnderstanding the disease at the cellular level helps explain why new treatments work. A normal artery has three layers: the innermost \u003cstrong\u003eintima\u003c\/strong\u003e (in direct contact with blood), the middle \u003cstrong\u003emedia\u003c\/strong\u003e (containing smooth muscle cells), and the outer \u003cstrong\u003eadventitia\u003c\/strong\u003e.\u003c\/p\u003e\n\n\u003cp\u003eUnder healthy conditions, the endothelial cells that line the intima do not attract blood leukocytes (white blood cells). But when activated by proinflammatory cytokines or other irritants related to cardiovascular risk factors, endothelial cells express adhesion molecules such as \u003cstrong\u003eVCAM-1\u003c\/strong\u003e, which interact with their partners (VLA4) on blood monocytes and lymphocytes. This causes the white blood cells to roll along the vessel surface, stick, and eventually migrate into the intima.\u003c\/p\u003e\n\n\u003cp\u003eWithin the intima, \u003cstrong\u003efoam cells\u003c\/strong\u003e—lipid-laden scavenger cells—form by taking up cholesterol. Some foam cells arise from blood monocytes that mature into macrophages. Remarkably, recent evidence in mice shows that \u003cstrong\u003esmooth muscle cells can undergo metaplasia\u003c\/strong\u003e (transform into a different cell type) and give rise to foam cells that carry markers identical to macrophages. T lymphocytes, though fewer in number, orchestrate many functions of these immune cells.\u003c\/p\u003e\n\n\u003cp\u003eAs the plaque grows, smooth muscle cells (both resident in the intima and migrated from the media) produce extracellular matrix—the structural \"scaffolding\" of the plaque. Growth factors like \u003cstrong\u003ePDGF\u003c\/strong\u003e promote smooth muscle migration and replication.\u003c\/p\u003e\n\n\u003cp\u003ePlaque progression reflects an ongoing struggle between factors that promote and those that mute the disease:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003ePro-inflammatory factors (promote disease):\u003c\/strong\u003e IL-1, TNF, M-CSF, and IFNγ (produced by Th1 cells) stimulate inflammation and plaque growth.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAnti-inflammatory factors (protect):\u003c\/strong\u003e IL-10 (from Th2 cells), TGFβ (from regulatory T cells), and natural IgM antibodies from B1 cells quell inflammation and promote tissue stability.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eA critical process called \u003cstrong\u003eefferocytosis\u003c\/strong\u003e—the engulfment of dying or dead cells by scavenger cells—helps keep plaques stable. When efferocytosis is inefficient, debris from dead cells accumulates, promoting the formation of the plaque's central lipid core. Researchers now view atherosclerosis as a years-long battle between proliferation and death, involving proinflammatory, anti-inflammatory, and pro-resolving mediators.\u003c\/p\u003e\n\n\u003ch2 id=\"bone-marrow\"\u003eThe Bone Marrow Connection: Clonal Haematopoiesis\u003c\/h2\u003e\n\n\u003cp\u003eOne of the most surprising recent discoveries links atherosclerosis to the bone marrow. As we age, we accumulate \u003cstrong\u003esomatic mutations\u003c\/strong\u003e (acquired, not inherited genetic changes) in the hematopoietic stem cells in our bone marrow—the cells that produce all blood cells. These mutations occur in genes that, when mutated, can also drive acute leukemia. However, researchers seeking the origins of leukemia found something unexpected: \u003cstrong\u003eapparently healthy individuals without any blood cancer can generate clones of leukocytes bearing these mutations\u003c\/strong\u003e in their circulating blood.\u003c\/p\u003e\n\n\u003cp\u003eThis condition is called \u003cstrong\u003eclonal haematopoiesis\u003c\/strong\u003e. It represents a previously unrecognized but common and potent age-related contributor to cardiovascular disease risk. The prevalence in individuals aged 70 \u003cstrong\u003eexceeds 10%\u003c\/strong\u003e, and the burden increases with further ageing. This discovery opens an entirely new window into why heart disease risk rises so dramatically with age—and may eventually lead to personalized screening or treatments targeting these mutated clones.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eClinical Implications: What This Means for Treatment\u003c\/h2\u003e\n\n\u003cp\u003eThis evolving understanding of atherosclerosis has opened multiple new avenues for prevention and treatment:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAnti-inflammatory therapy is now proven.\u003c\/strong\u003e The CANTOS, COLCOT, and LoDoCo2 trials demonstrate that modulating inflammation reduces cardiovascular events independent of cholesterol lowering. Colchicine is already becoming part of standard care for selected patients after heart attacks. Because canakinumab increased infections, its use requires careful patient selection, but the lung cancer finding suggests intriguing possibilities.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTriglyceride-rich lipoproteins are a treatment target.\u003c\/strong\u003e The strong human genetic evidence that TGRL cause atherosclerosis has renewed interest in therapies that lower TGRL, including drugs targeting apolipoprotein CIII, ANGPTL3, and ANGPTL4—the proteins that inhibit lipoprotein lipase.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLipoprotein(a) is on the radar.\u003c\/strong\u003e With convincing genetic evidence of causality, new drugs targeting lipoprotein(a) are in development. This is particularly important for patients with a family history of early heart disease or aortic valve disease.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGenetic risk scores may enable earlier prevention.\u003c\/strong\u003e Because genetic risk can be detected from birth, these scores may inform early, targeted prevention strategies in younger individuals with an inherited predisposition. Importantly, \u003cstrong\u003elifestyle measures appear to mitigate cardiovascular risk across the entire spectrum of genetic risk\u003c\/strong\u003e—so even those with high genetic risk can benefit from healthy habits.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eClonal haematopoiesis may become a biomarker.\u003c\/strong\u003e Testing for these bone marrow mutations could someday identify older adults at especially high cardiovascular risk, potentially guiding more aggressive prevention.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eOne important caveat: genetic risk scores' ability to improve prediction of events beyond traditional algorithms remains controversial, so they are not yet ready for routine clinical use in all settings.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations: What We Still Don't Know\u003c\/h2\u003e\n\n\u003cp\u003eThis review article synthesizes current knowledge, but important uncertainties remain:\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eHDL's role is not fully settled.\u003c\/strong\u003e Although raising HDL cholesterol has failed to reduce events, the functional properties of HDL (cholesterol efflux, anti-inflammatory actions) may still protect. Standard blood tests may not capture these functions.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAnimal models don't perfectly mirror human disease.\u003c\/strong\u003e For example, humans (but not many small laboratory animals) have resident smooth muscle cells in the intima, which affects how plaques develop. Some findings in mice may not translate to humans.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAnti-inflammatory treatments have side effects.\u003c\/strong\u003e Both canakinumab (increased infections) and colchicine (more than doubled pneumonia incidence) carry risks that must be weighed against benefits.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eGenetic risk scores remain controversial\u003c\/strong\u003e in their ability to improve prediction beyond traditional risk calculators.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eObservational associations\u003c\/strong\u003e (such as those linking air pollution, noise, and disturbed sleep to heart disease) cannot prove causation, although the inflammatory mechanisms provide plausible biological explanations.\u003c\/li\u003e\n  \u003cli\u003eThe \u003cstrong\u003etrajectory of prevention is uncertain\u003c\/strong\u003e: the slowing or halting of heart disease decline in some US and UK regions between 2014 and 2019 suggests that current prevention strategies may be losing ground against rising obesity and other modern exposures.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations for Patients\u003c\/h2\u003e\n\n\u003cp\u003eBased on this evolving science, here are practical steps patients can discuss with their healthcare team:\u003c\/p\u003e\n\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eKnow your numbers beyond LDL.\u003c\/strong\u003e Ask about your triglyceride level and, if you have a family history of early heart disease or aortic valve problems, ask whether testing for lipoprotein(a) is appropriate. TGRL (triglyceride-rich lipoproteins) are now recognized as causal risk factors, not just bystanders.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDon't stop your statin or other LDL-lowering therapy.\u003c\/strong\u003e LDL remains a definitive cause of atherosclerosis. Reducing lifelong exposure to elevated LDL is fundamental—even in the era of anti-inflammatory drugs.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eAsk about inflammation.\u003c\/strong\u003e A simple blood test for hsCRP can gauge inflammatory status. If your hsCRP is elevated despite good cholesterol control, talk with your doctor about whether anti-inflammatory strategies—such as low-dose colchicine—might be appropriate, particularly if you've already had a cardiovascular event.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eProtect your sleep.\u003c\/strong\u003e Disturbed sleep is increasingly recognized as a contributor to cardiovascular risk, in part through inflammatory pathways. Prioritizing good sleep hygiene is a low-cost, evidence-informed strategy.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eManage abdominal weight.\u003c\/strong\u003e Excess fat around the abdomen (visceral adiposity) and fatty liver drive insulin resistance and inflammation. Even modest weight loss can meaningfully reduce metabolic risk. Remember that people of Asian, South Asian, and Central\/South American descent may develop metabolic problems at lower waist measurements than white individuals—so don't rely on one-size-fits-all thresholds.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eMinimize environmental exposures where possible.\u003c\/strong\u003e Air pollution, environmental noise, and second-hand smoke all contribute to cardiovascular risk. Reducing exposure—through air purifiers, avoiding high-traffic areas during peak pollution, or noise protection—may help.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eLimit sugar-sweetened beverages.\u003c\/strong\u003e Drinks high in fructose contribute to obesity and its adverse metabolic consequences. This is one of the most readily remedied dietary shifts.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eKnow that lifestyle helps at every genetic risk level.\u003c\/strong\u003e Even if you carry a high genetic risk score, lifestyle measures mitigate risk across the entire spectrum of genetic predisposition. Genes are not destiny.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eIf you've had a heart attack, don't underestimate residual risk.\u003c\/strong\u003e Even on optimal therapy, about 1 in 20 patients will have another event within a year, and 1 in 10 survivors of acute heart attack in the US are readmitted within a month. Staying on all prescribed medications and attending cardiac rehabilitation are critical.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is atherosclerosis and why does it matter?\u003c\/h3\u003e\n\u003cp\u003eAtherosclerosis is the buildup of cholesterol, fat, and inflammatory cells inside artery walls. Plaques can narrow blood vessels or rupture, causing blood clots. It is the underlying cause of heart attacks, heart failure, strokes, and peripheral artery disease. Many people do not know they have it until a serious event happens.\u003c\/p\u003e\n\u003ch3\u003eI already had a heart attack. Even with treatment, how likely is another one?\u003c\/h3\u003e\n\u003cp\u003eIn recent clinical trials, about 1 in 20 patients had a recurrent heart attack, stroke, or cardiac event within a year after an acute coronary syndrome, despite optimal standard therapy. In the United States, 1 in 10 heart attack survivors is readmitted to the hospital within one month. Staying on medications and attending cardiac rehabilitation are critical.\u003c\/p\u003e\n\u003ch3\u003eIs LDL cholesterol the only cholesterol that causes heart disease?\u003c\/h3\u003e\n\u003cp\u003eLDL cholesterol definitively causes atherosclerosis. However, triglycerides and triglyceride-rich lipoproteins are now recognized as causal risk factors too. Lipoprotein(a), a genetic form of LDL, also causes atherosclerosis and aortic valve disease. Ask your doctor about your triglyceride level and, if you have a family history of early heart disease, whether testing for lipoprotein(a) is appropriate.\u003c\/p\u003e\n\u003ch3\u003eWhat is the hsCRP blood test and why does it matter?\u003c\/h3\u003e\n\u003cp\u003ehsCRP stands for high-sensitivity C-reactive protein, a blood test that measures overall innate immune activity and inflammation. It is a validated, clinically useful gauge of atherosclerotic risk, even independently of traditional risk factors. If your hsCRP is elevated despite good cholesterol control, discuss anti-inflammatory strategies with your doctor, especially if you have already had a cardiovascular event.\u003c\/p\u003e\n\u003ch3\u003eCan anti-inflammatory drugs reduce heart attack risk?\u003c\/h3\u003e\n\u003cp\u003eYes. In the CANTOS, COLCOT, and LoDoCo2 trials, anti-inflammatory therapies reduced recurrent cardiovascular events in patients already on optimal cholesterol and blood pressure treatment. Colchicine reduced events by 23% in early post-heart-attack patients. However, these drugs have side effects, including increased infections, so they are not for everyone. Ask your doctor if you are a candidate.\u003c\/p\u003e\n\u003ch3\u003eWhat can I do about belly fat, sleep, and sugary drinks?\u003c\/h3\u003e\n\u003cp\u003eExcess abdominal fat and fatty liver drive insulin resistance and inflammation, increasing heart risk. Disturbed sleep is a contributor. Sugar-sweetened beverages high in fructose contribute to obesity. Even modest weight loss helps. People of Asian, South Asian, and Central or South American descent may develop metabolic problems at lower waist measurements, so do not rely on one-size-fits-all thresholds.\u003c\/p\u003e\n\u003ch3\u003eShould I be tested for lipoprotein(a) if heart disease runs in my family?\u003c\/h3\u003e\n\u003cp\u003eElevated lipoprotein(a) is a genetic risk factor that causes both atherosclerosis and calcific aortic valve disease. It is not something you can change through diet or exercise, but targeted therapies are in development. If you have a family history of early heart disease or aortic valve problems, ask your healthcare team whether testing is appropriate.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003eThis patient-friendly article is based on a peer-reviewed scientific review published in the journal \u003cem\u003eNature\u003c\/em\u003e.\u003c\/p\u003e\n\n\u003cul\u003e\n  \u003cli\u003e\n\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e The changing landscape of atherosclerosis\u003c\/li\u003e\n\u003c\/ul\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47439661695132,"sku":null,"price":0.0,"currency_code":"EUR","in_stock":true}],"url":"https:\/\/diagnosticdetectives.cn\/products\/the-changing-landscape-of-atherosclerosis-what-every-patient-should-know","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}