Cardiovascular disease is caused by a combination of metabolic, behavioral, genetic, and environmental factors that damage blood vessels over time. It killed an estimated 19.8 million people in 2022, accounting for roughly 32% of all deaths worldwide, with 85% of those deaths due to heart attack and stroke. Understanding what drives this damage helps explain why some people develop heart disease decades earlier than others.
How Blood Vessel Damage Begins
Nearly every form of cardiovascular disease traces back to damage in the inner lining of your arteries, a thin layer of cells called the endothelium. This lining acts as a gatekeeper: it keeps blood flowing smoothly, prevents clots from forming unnecessarily, and signals the artery walls to relax or tighten as needed. When something disrupts this lining, the chain reaction toward heart disease begins.
The earliest measurable change is a drop in the lining’s ability to produce nitric oxide, a molecule that keeps arteries relaxed and open. Without enough nitric oxide, arteries start to stiffen and narrow. The damaged lining also becomes more permeable, allowing cholesterol particles to slip underneath it and lodge in the artery wall. White blood cells follow, swallowing the trapped cholesterol and swelling into foam cells. Smooth muscle cells in the artery wall begin to multiply and migrate into the growing mass. Over years, this buildup hardens into plaque, a process called atherosclerosis.
What makes this process dangerous is that it feeds itself. Oxidized LDL cholesterol suppresses nitric oxide production even further, which accelerates plaque growth. Inflammatory signals from the plaque recruit more immune cells, which release substances that make the plaque unstable. If the plaque’s surface cracks open, a blood clot forms instantly at the site. That clot can block the artery completely, causing a heart attack or stroke.
High Blood Pressure
Sustained high blood pressure is one of the most potent drivers of cardiovascular disease because it physically batters the artery lining with every heartbeat. Clinical guidelines define blood pressure in escalating risk categories: optimal is below 120/80, nonoptimal ranges from 120 to 139 over 80 to 89, elevated spans 140 to 159 over 90 to 99, and major risk begins at a systolic reading of 160 or above. Each step up the ladder increases the mechanical stress on artery walls, accelerating the endothelial damage that leads to plaque formation. High blood pressure also forces the heart to pump harder, which over time thickens the heart muscle and can lead to heart failure.
High Cholesterol and Blood Lipids
LDL cholesterol is the primary raw material of arterial plaque. When levels are chronically elevated, more LDL particles penetrate the artery lining, triggering the inflammatory cascade described above. Once LDL particles are trapped in the artery wall, they become oxidized, which makes them far more damaging. Oxidized LDL directly blocks the production of nitric oxide and stimulates smooth muscle cells to grow into the developing plaque.
HDL cholesterol works in the opposite direction, pulling cholesterol out of artery walls and ferrying it back to the liver. A low HDL level means less of this cleanup is happening. Triglycerides, another blood fat, contribute independently by promoting inflammation and making LDL particles smaller and denser, which lets them penetrate artery walls more easily.
Diabetes and Insulin Resistance
People with diabetes develop cardiovascular disease earlier and more aggressively than the general population. Persistently elevated blood sugar damages arteries through at least three distinct pathways. First, excess glucose attaches to proteins throughout the body, forming compounds called advanced glycosylated end-products. These altered proteins stiffen artery walls, trigger inflammation, and generate reactive oxygen species that destroy the protective nitric oxide in blood vessel linings.
Second, high glucose activates an enzyme called protein kinase C, which triggers a cascade of problems: it promotes the production of substances that constrict blood vessels, stimulates inflammatory adhesion molecules on the artery lining, and shifts smooth muscle and endothelial cells into a growth mode that accelerates plaque formation. The common thread across all these pathways is oxidative stress, which impairs the artery lining’s ability to function and sets the stage for early, widespread atherosclerosis. Gestational diabetes carries lasting consequences too: it increases the lifetime risk of developing type 2 diabetes by sevenfold and nearly doubles cardiovascular disease risk.
Smoking and Tobacco Use
Smoking damages the cardiovascular system on multiple fronts simultaneously. The chemicals in tobacco smoke directly injure the endothelial lining, reduce nitric oxide availability, increase oxidative stress, and make blood more prone to clotting. Nicotine raises heart rate and blood pressure, increasing the workload on the heart. Carbon monoxide displaces oxygen in the blood, forcing the heart to pump harder to deliver adequate oxygen to tissues. These effects are not limited to heavy smokers. Even low levels of exposure, including secondhand smoke, measurably increase cardiovascular risk.
Diet, Inactivity, and Obesity
What you eat shapes cardiovascular risk in ways that go beyond cholesterol numbers. Diets high in ultra-processed foods (packaged snacks, sugary drinks, processed meats, ready-to-eat meals) are linked to a 25% to 58% higher risk of cardiometabolic disease and a 21% to 66% higher risk of death, compared with low intake. These foods tend to be high in sodium, added sugars, and industrial fats while being low in fiber, potassium, and protective plant compounds.
Physical inactivity compounds the dietary risk. The current guideline for cardiovascular protection is 150 minutes per week of moderate-intensity activity like brisk walking, or 75 minutes of vigorous activity like jogging. Benefits increase beyond those thresholds. Regular exercise lowers blood pressure, improves cholesterol balance, enhances insulin sensitivity, and reduces chronic inflammation. Sedentary behavior does the opposite of all four.
Excess body fat, particularly visceral fat stored around the organs, acts as an active endocrine tissue that pumps out inflammatory signals. This chronic low-grade inflammation damages artery linings and promotes insulin resistance, creating a feedback loop that worsens metabolic health over time.
Genetic and Inherited Factors
Some people inherit a significantly elevated cardiovascular risk regardless of lifestyle. Familial hypercholesterolemia, a genetic condition affecting roughly 1 in 250 people, causes dangerously high LDL cholesterol from birth. Without treatment, people with this condition can develop heart disease in their 30s or 40s.
Lipoprotein(a), often written as Lp(a), is a genetically determined particle that promotes clotting and inflammation. Levels at or above 125 nmol/L increase the risk of heart attack and stroke. At 250 nmol/L or higher, that risk roughly doubles. Unlike regular cholesterol, Lp(a) levels are largely fixed by your genes and don’t respond much to diet or standard cholesterol-lowering approaches. Most people have never had their Lp(a) tested because it isn’t included in routine bloodwork, but a single lifetime measurement can reveal this hidden risk factor.
Chronic Inflammation
Inflammation isn’t just a consequence of plaque formation. It’s a driver. People with chronically elevated levels of systemic inflammation face higher cardiovascular risk even when their cholesterol and blood pressure look normal. A blood test measuring high-sensitivity C-reactive protein (hs-CRP) captures this: levels below 1 mg/L indicate low vascular risk, 1 to 3 mg/L indicates moderate risk, and 3 mg/L or above signals high risk. Conditions that fuel chronic inflammation, including autoimmune diseases like rheumatoid arthritis and lupus, gum disease, and chronic infections, all independently raise the odds of cardiovascular events.
Air Pollution
Fine particulate matter (PM2.5), the tiny particles released by vehicle exhaust, industrial processes, and wildfire smoke, is an increasingly recognized cardiovascular risk factor. These particles are small enough to pass from the lungs into the bloodstream, where they trigger systemic inflammation, promote blood clotting, impair artery dilation, and raise blood pressure. Long-term exposure accelerates atherosclerosis in much the same way that metabolic risk factors do. Roughly 80% of global cardiovascular deaths occur in low- and middle-income countries, where air pollution exposure and limited access to treatment often overlap.
Risks Specific to Women
Women face several cardiovascular risk factors that don’t apply to men. About 15% of women who give birth experience a hypertensive complication during at least one pregnancy, and these complications carry lasting consequences. A history of high blood pressure during pregnancy increases the risk of coronary heart disease by 80% and heart failure by 70% later in life. Preeclampsia specifically doubles the risk of a type of heart failure in which the heart muscle stiffens rather than weakens.
Polycystic ovary syndrome (PCOS) triples the risk of type 2 diabetes and up to doubles cardiovascular disease risk. Even reproductive history matters in unexpected ways: both very early and very late onset of menstruation are associated with higher cardiovascular risk later in life, and spontaneous pregnancy loss is linked to a 21% increased risk of cardiovascular disease after adjusting for other factors. These sex-specific risks mean that a woman’s obstetric and reproductive history is a meaningful part of her cardiovascular risk profile, not a separate medical category.