Cardiovascular Disease

Cardiovascular disease (CVD) is a group of disorders of the heart and blood vessels. It includes coronary heart disease, cerebrovascular disease (stroke), peripheral arterial disease, rheumatic heart disease, and congenital heart disease, among others. Most of its common forms share a single underlying process: atherosclerosis and related damage to the vessel wall and heart muscle, which build up over years before they produce a heart attack, stroke, or organ failure. Because the circulatory system delivers oxygen and nutrients to every tissue, these conditions affect nearly every organ. They are a central subject of medicine, physiology, and public-health. According to the World Health Organization, CVD is the leading cause of death worldwide, and an estimated 19.8 million people died from it in 2022, about 32% of all global deaths, with more than three quarters of these deaths occurring in low- and middle-income countries. Its importance lies both in its scale and in the fact that much of the burden is preventable.

This entry first defines the term and describes the normal structure and function of the cardiovascular system, so that the disorders can be understood in their physiological context. It then examines the major disease categories in turn: the atherosclerotic processes behind coronary disease and stroke, hypertension, heart failure and arrhythmias, valvular and congenital disease, and peripheral vascular disorders. Risk factors, genetic and molecular mechanisms, and global epidemiology come next, followed by diagnosis, prevention and treatment, and the health-policy response. The entry closes with the history of research that shaped current understanding, the variation of risk across sex, age, and population groups, and the questions that remain open.

Definition and classification

Cardiovascular disease (CVD) is an umbrella label rather than the name of a single illness. The WHO applies it to conditions that share an anatomical site, the heart and the vascular network, but not a common cause or course. Cardiovascular diseases are described as a group of disorders of the heart and blood vessels. The label persists because its members differ widely in age of onset, mechanism and treatment. A congenital valve malformation in an infant and coronary atherosclerosis in an older adult share little beyond location. In everyday speech, "heart disease" is often shorthand for coronary disease, which is why the broader term is needed in clinical and epidemiological writing. In most cases, when someone says "heart disease," they're referring to coronary heart disease.

The principal categories are usually defined by the organ or vessel involved. Coronary heart disease affects the vessels supplying the heart muscle, cerebrovascular disease affects those supplying the brain, and peripheral arterial disease affects those supplying the arms and legs. Rheumatic heart disease involves damage to the heart muscle and valves, and congenital heart disease arises from structural malformations present from birth. Rheumatic heart disease is a sequel of an abnormal immune response to infection with streptococcal bacteria, which usually begins as a sore throat or tonsillitis. Hypertensive heart disease is recognised mainly through coding rules: certain heart conditions are assigned to hypertensive heart disease when a causal relationship to hypertension is stated or implied. Other lists add heart failure, arrhythmias, cardiomyopathy and valve disease, and some include deep vein thrombosis and pulmonary embolism, which are blood clots in the leg veins that can dislodge and travel to the heart and lungs.

The categories also cut across mechanisms. Atherosclerosis, the build-up of plaque within arterial walls, is the primary underlying cause of many CVDs, and it can lead to coronary artery disease, cerebrovascular disease and other vascular conditions. Structural disorders, such as congenital defects and degenerative valve disease, arise from malformation or wear of the cardiac tissue itself. Electrical disorders, such as arrhythmias, stem from abnormal impulse generation or conduction. Thrombotic disorders, such as venous thromboembolism and cardioembolic stroke, involve clot formation and migration. These mechanisms overlap in practice. Atrial fibrillation is an electrical disorder, yet it can produce emboli that cause a thrombotic stroke, so a single patient may belong to several categories at once.

Counting CVD depends on the measure chosen. Mortality statistics count deaths in which a cardiovascular condition is the recorded cause. An estimated 19.8 million people died from CVDs in 2022, about 32% of all global deaths, and 85% of those deaths were due to heart attack and stroke. Prevalence statistics instead count people living with a condition at a given time, and these figures are far larger. In 2021, the global prevalence of CVD was estimated at 612.06 million. The two measures answer different questions. A person with long-standing coronary disease may be counted in prevalence for decades and then appear in mortality statistics under a different cause, such as stroke or heart failure. Estimates also vary between sources partly because they refer to different years and use different estimation methods. The American Heart Association's 2021 figure of approximately 19.41 million global deaths attributed to CVD is therefore not directly comparable with the WHO's 2022 figure.

Classification rules shape these numbers as well. The International Classification of Diseases is used to classify causes of death so that reporting is comparable among health systems. Chapter placement matters. In ICD-11, cerebrovascular diseases are coded in a separate chapter rather than under circulatory diseases, which means that the same stroke may be classified differently across revisions and national systems. Hypertensive heart disease and heart failure also carry specific coding conventions. Because death certificates typically record one underlying cause, decisions about coding practice can change reported totals even when the underlying disease burden is unchanged.

Normal structure and function of the cardiovascular system

The heart and its conduction system

The adult heart has four chambers: two atria that receive blood and two ventricles that eject it. The right side pumps blood to the lungs at low pressure, while the thicker-walled left ventricle drives blood through the systemic circuit. Four valves keep flow one-directional. The tricuspid and mitral valves lie between the atria and ventricles, and the pulmonary and aortic valves guard the outflow arteries.

Contraction is coordinated by a specialised electrical system. Spontaneous depolarisation of pacemaker cells in the sinoatrial (SA) node, at the junction of the right atrium and the superior vena cava, sets the resting rate, typically 60 to 100 beats per minute. The impulse spreads across both atria, causing them to contract, and reaches the atrioventricular (AV) node in the lower atrial septum. The AV node slows conduction by a fraction of a second, so the atria can empty into the ventricles before those chambers contract. The impulse then travels down the bundle of His, which divides into left and right bundle branches that end in Purkinje fibres spreading through the ventricular walls. Under normal conditions the bundle of His is the only electrical link between atria and ventricles, because the fibrous skeleton of the heart insulates the two. If the SA node fails, the AV node and Purkinje fibres can take over, but at progressively slower intrinsic rates. Sympathetic input speeds the SA node, while parasympathetic (vagal) input slows it. Pacemaker activity depends on slow inward currents through ion channels, whereas the rapid upstroke of ventricular cells depends on fast sodium channels, a difference that shapes the action potential of each tissue.

Systemic and pulmonary circuits and vessel walls

The two circuits operate in series. In the pulmonary circuit, the right ventricle sends blood through the pulmonary arteries to the lungs, where it takes up oxygen and releases carbon dioxide; it then returns via the pulmonary veins to the left atrium. In the systemic circuit, the left ventricle delivers blood to the aorta, which branches into arteries, arterioles, capillaries, venules, and veins, ending in the vena cavae that return blood to the right atrium. Because the pulmonary circuit is a low-pressure system, the right ventricular wall is much thinner than the left.

The wall structure of each vessel type reflects its function. Arteries have three layers: an inner intima, a media of smooth muscle and elastic fibres, and an outer adventitia. Large elastic arteries such as the aorta have a media rich in elastin, which lets them stretch during systole and recoil during diastole, smoothing the pulsatile flow. Muscular arteries have more smooth muscle and help distribute flow. Arterioles, with a strong smooth-muscle layer, are the main sites of resistance. Capillaries consist of a single endothelial layer on a basement membrane, which makes them the site of exchange with tissues. Veins have thinner walls, operate at lower pressure, hold a large share of the blood volume, and in the limbs contain valves that prevent backflow.

Regulation of blood pressure

Mean arterial pressure is approximately the product of cardiac output and total peripheral resistance. Cardiac output equals heart rate multiplied by stroke volume, and peripheral resistance is determined mainly by arteriolar diameter. Any change in one of these variables alters pressure, so the body adjusts them together. Baroreceptors in the carotid sinus and aortic arch detect stretch and signal the brainstem, which modulates sympathetic and parasympathetic outflow. Sympathetic activation raises heart rate and contractility, constricts arterioles, and stimulates renin release.

The renin–angiotensin system acts over a longer timescale. Juxtaglomerular cells in the kidney release renin when renal perfusion pressure falls or when sodium delivery to the distal tubule declines. Renin acts on angiotensinogen, and angiotensin-converting enzyme (ACE) then converts angiotensin I to angiotensin II. Angiotensin II constricts arterioles, stimulates aldosterone secretion from the adrenal cortex to promote sodium and water retention, and triggers release of vasopressin, a hormone whose release is controlled by the hypothalamus. It also increases sympathetic output from the brain. Together these actions make the system one of the strongest regulators of arterial pressure.

The endothelium as an active organ

The endothelium is a single layer of cells lining the heart chambers and all blood vessels, and in humans its total surface area exceeds 3,000 square metres. It is not a passive barrier. Endothelial cells make nitric oxide from L-arginine through endothelial nitric oxide synthase. Nitric oxide diffuses into smooth muscle, raises cyclic GMP, and relaxes the vessel. It also inhibits platelet adhesion and aggregation, leukocyte adhesion, and smooth-muscle proliferation. Prostacyclin contributes to vasodilation and platelet inhibition, while endothelin-1 is a potent vasoconstrictor, so the balance between these mediators sets vascular tone. The surface also carries anticoagulant mechanisms, including thrombomodulin, which activates protein C.

Under inflammatory stimulation, endothelial cells express adhesion molecules and chemokines that recruit leukocytes and macrophages, and they release cytokines that amplify the response. Endothelial dysfunction is generally defined as a reduction in bioavailable nitric oxide. It occurs early, often in people with hypertension, lipid disorders, smoking, or diabetes, before structural lesions appear, and it is considered an independent predictor of cardiovascular risk.

Atherosclerosis and its progression

Lipoprotein entry and early lesions

Atherosclerosis begins when low-density lipoprotein (LDL) particles cross a damaged endothelium and enter the intima, and the modified particles are then taken up by the wall's cells. Inside the intima, proteoglycans in the extracellular matrix hold the particles in place. Because their chains are negatively charged, they attract the positively charged form of LDL and keep it from washing away. Low-density lipoprotein (LDL), which is present in the bloodstream, enters the intima through the damaged endothelium and undergoes modification to become oxidized LDL (oxLDL). The retention itself is initiated by the retention of low-density lipoproteins (LDLs), positively charged, by negatively charged glucosaminoglycans (GAGs) of proteoglycans (PGs).

Oxidised particles then act as an inflammatory trigger. Endothelial cells respond to them by releasing signalling molecules, including the chemoattractant MCP-1, which draw circulating monocytes into the wall. Once in the intima, these monocytes mature into macrophages that engulf the lipid. This is how the inflammatory process becomes self-sustaining: the lipid-laden cells release further cytokines and chemoattractants, which recruit still more monocytes. Lipid-laden macrophages become foam cells, that is, large cells which are filled with lipid droplets that give them a foamy appearance. These foam cells are the building blocks of the earliest lesions. Their accumulation forms the first macroscopic appearance of atherosclerosis, known as a fatty streak, and such changes can start in adolescence and have been shown to be predictive of occlusive vascular events.

Plaque growth and structure

Macrophages were long considered the main source of foam cells, but lineage-tracing studies in mice have shown that smooth muscle cells (SMCs) are also an important source. They are the first foam cells in a lesion and form the majority of foam cells in advanced plaques. Estimates in one review place 30% to 70% of the total foam cells within the plaque of both mice and humans as derived from SMCs. As lesions mature, after apoptosis, foam cells form the lipid-rich necrotic core, and contribute to the volume growth of the intima eventually restricting the artery lumen. A necrotic core that sits beneath a fibrous cap of collagen, with macrophages scattered through it, is the defining feature of the advanced lesion. In a pathology review, the precursor of rupture is the "thin-cap fibroatheroma" (TCFA), which is marked by a large necrotic core and an unusually thin cap.

Narrowing of the lumen is not a simple, linear process. Early plaques often expand outward into the wall rather than into the channel, so a lesion can grow for years without causing significant obstruction. This is one reason that the degree of stenosis is a poor predictor of acute events.

Rupture, erosion, and thrombosis

Acute coronary events are driven mainly by thrombosis. In plaque rupture, a thin cap tears and exposes highly reactive lipid material to flowing blood. Plaque rupture is defined as a lesion consisting of a necrotic core with an overlying thin ruptured fibrous cap that leads to luminal thrombosis because of contact of platelets with a highly thrombogenic necrotic core. Autopsy studies have found that 70% to 80% of coronary thrombi occur at sites where the fibrous cap of an atherosclerotic plaque has fissured or ruptured, and the thrombus often extends both into the plaque and into the lumen.

Erosion is a distinct route in which the cap remains intact. Plaque erosion shows a luminal thrombus with an underlying base rich in proteoglycans and smooth muscle cells with minimal inflammation. Rupture remains the most common cause of coronary thrombosis, followed by erosion, and calcified nodules are rare. Rupture is also the dominant cause of acute coronary syndromes, and a review cites that ruptured lesions are responsible for the majority (73%) of all ACSs.

Many ruptures and erosions produce no immediate symptoms. Short-term risk therefore depends on more than the size of the narrowing. The vulnerable patient is a term used to describe patients at high short-term risk of an acute clinical event. This depends on plaque burden, plaque vulnerability, systemic thrombotic propensity, and the myocardial susceptibility to ischemia and arrhythmia.

Stable and vulnerable plaque

Plaques at risk of rupture tend to enlarge outward, carry a large lipid pool beneath a thinned cap with less collagen, and contain dense inflammatory infiltrates. Plaque stabilization through change in plaque composition may be responsible for reduced frequency of acute vaso-occlusive events observed with lipid and other risk-factor modifying interventions. The term "vulnerable plaque" is used in two ways. It may refer broadly to any plaque likely to clot, or narrowly to a set of histological features assumed to predict imminent rupture. The latter usage explains why the vulnerable plaque term is also used in research with mouse models, where the occurrence of thrombosis on plaques is exceedingly rare.

Imaging has made it possible to study these lesions in living patients, but its categories need careful interpretation. In one study of patients with acute coronary syndromes, optical coherence tomography (OCT) classified 31% of the lesions as erosion and 8% as calcified nodules. However, OCT has limits: the definitions of plaque erosion and calcified nodule as detected by OCT were not validated by pathology. Its resolution also cannot resolve a single endothelial layer, so pathological criteria cannot be applied to it directly. Pathology and imaging must therefore be read together.

Coronary heart disease and myocardial infarction

From narrowing to ischaemia

Coronary heart disease usually begins with atherosclerotic plaque that narrows the epicardial arteries over years. A fixed narrowing limits how much blood the myocardium can receive during exertion, so when demand rises, the heart muscle receives less oxygen than it needs. Because cardiac muscle already extracts most of the oxygen in arterial blood at rest, it depends heavily on increasing coronary flow to meet extra demand. The result is ischaemia, which typically causes chest discomfort on exertion that eases with rest or nitrates. This is stable angina. Symptoms that occur at rest, are new or increasing in frequency, or appear suddenly point instead to an acute coronary syndrome (ACS), in which the plaque has changed and a thrombus forms on it, as described in the section on plaque rupture.

The pathophysiology of infarction

Myocardial infarction is myocardial necrosis caused by prolonged ischaemia. Experimental work from the 1970s and 1980s showed that when a coronary artery is occluded, injury begins in the subendocardium, the layer of muscle furthest from the blood supply, and then spreads outward as a wavefront over several hours. Within that window, cardiomyocytes deprived of oxygen shift to anaerobic metabolism, lose ionic homeostasis, and die. This is why the duration of occlusion, and not only its severity, determines how much muscle is lost.

Reperfusion, whether by antiplatelet therapy, thrombolysis, or primary percutaneous coronary intervention, is the main way to limit this loss. The principle that time matters is captured in the phrase "time is muscle": the amount of myocardium that can still be saved falls as the interval from symptom onset to reopening lengthens. Restoring flow is not without cost, however. Reperfused tissue can suffer additional injury through the release of reactive oxygen species, calcium overload, and mitochondrial dysfunction, which can drive programmed cell death. This might lead to complications such as no-reflow phenomenon, myocardial stunning, malignant arrhythmias, and heart failure. Microvascular obstruction, in which small vessels are blocked by debris after the main artery is reopened, is a further reason why successful reperfusion does not always translate into full recovery.

STEMI and NSTEMI

Acute coronary syndromes are divided primarily by the electrocardiogram. In ST-elevation myocardial infarction (STEMI), the overlying thrombus is extensive enough to fully occlude the coronary artery lumen, producing transmural injury across the full thickness of the wall. In non-ST-elevation myocardial infarction (NSTEMI), the thrombus is partly obstructive and the infarct is usually confined to the subendocardium. Even so, approximately 25% of NSTEMI are associated with a total occlusion of a coronary artery or branch and thus have the potential to become transmural if treatment is delayed. The two categories also differ in their treatment logic: a STEMI is an indication for immediate reperfusion, whereas NSTEMI is managed with antithrombotic therapy and an invasive assessment that is usually done within a day or two.

The diagnosis of myocardial infarction requires a rise in a cardiac biomarker. These conditions can be satisfied by a rise of cardiac troponin (cTn) above the 99th percentile of the upper reference limit (URL) plus at least one of the following, such as symptoms of ischaemia or new ECG changes. Troponin is the central marker in NSTEMI because ECG findings are nonspecific, serum troponin elevation is the primary diagnostic finding in that setting. Troponin concentrations also depend on the time since symptom onset and on patient characteristics, and studies suggest that STEMI and NSTEMI show different release patterns, which is why they are often analysed separately. The fourth universal definition also recognises type 2 infarction, in which an oxygen supply–demand mismatch, rather than plaque rupture, causes the troponin rise.

Remodelling, scarring, and long-term consequences

Infarction triggers a healing process that begins with inflammation and ends with scar formation. Necrotic muscle is replaced by collagen-dense fibrosis. Scarring is essential for preventing rupture of the ventricular wall, but the scar itself is non-contractile. In the weeks after infarction, collagen fibres are morphologically evident at week 1 post-MI, while an organized assembly of these fibres in the form of scar tissue becomes evident at week 2. Over the following weeks the scar matures.

Adverse remodelling then changes the shape and function of the whole ventricle. Postinfarct remodelling is a specific type of left ventricular remodelling that is a consequence of an increase in both preload and afterload causing an enlargement of ventricular chamber and a hypertrophy of normal myocardium, and the scar may thin and expand under pressure. Ejection fraction can look preserved in the early months, so these changes are not always visible on simple measurements. Left ventricular dilatation and the extent of scarring are the main predictors of later heart failure.

The scar also affects electrical stability. Fibrosis creates conduction barriers that encourage re-entrant circuits. The amount of fibrotic scar in the myocardium correlates strongly with the increased incidence of arrhythmias and sudden cardiac death. Ventricular tachycardia or fibrillation can occur immediately after infarction, during remodelling, or long after the event. Patients with post-infarction left ventricular ejection fraction below 35% are generally considered to be at high risk of sudden cardiac death. Treatment of the long-term phase therefore includes drugs that slow remodelling, such as ACE inhibitors and angiotensin receptor blockers, beta-blockers, and, where indicated, implantable defibrillators or catheter ablation of arrhythmic substrate. The long-term course is therefore shaped by both the size of the infarct and how the surrounding myocardium adapts.

Stroke and cerebrovascular disease

Stroke is a sudden interruption of blood flow to the brain, and it is best understood as two different disease processes. In ischemic stroke, a vessel supplying the brain is occluded, most often by a thrombus formed in situ or an embolus carried from elsewhere, so downstream tissue loses its oxygen and glucose supply. In hemorrhagic stroke, a vessel ruptures and blood accumulates within brain tissue (intracerebral hemorrhage, ICH) or in the subarachnoid space (subarachnoid hemorrhage, SAH). Ischemic stroke makes up the large majority of cases, although the proportions vary between populations. Hemorrhagic strokes account for a disproportionate share of deaths and disability relative to their numbers, because bleeding raises intracranial pressure and tends to cause more severe primary damage.

Transient ischemic attack (TIA) is a brief episode of focal neurological symptoms caused by temporary reduction of blood flow, without permanent infarction on imaging. It is a warning sign: a substantial proportion of people with TIA go on to have a stroke, many within days. Small-vessel disease, sometimes called lacunar stroke, affects the penetrating arterioles deep in the brain. Chronic hypertension and diabetes thicken and damage these vessels, producing small infarcts in subcortical white matter and the basal ganglia, and it is a major cause of vascular cognitive impairment. Atrial fibrillation is a leading source of cardioembolic stroke: blood stagnating in the fibrillating left atrium, particularly the appendage, can form clots that travel to cerebral arteries, and such events are often large and severe. Carotid atherosclerosis contributes in a different way, with plaque at the carotid bifurcation either shedding emboli or narrowing the lumen enough to reduce flow. Both mechanisms are discussed in detail in the atherosclerosis and arrhythmia sections of this entry.

Time dependence and the ischemic penumbra

The central concept in acute ischemic stroke is the ischemic penumbra: tissue around the dead core that is severely hypoperfused and has stopped functioning, yet is not yet irreversibly infarcted. Because penumbral neurons can recover if flow is restored, the aim of acute treatment is to reperfuse the brain before the core expands into them. The penumbra evolves at a variable rate, and the rate depends largely on the quality of collateral circulation, particularly leptomeningeal anastomoses. Some patients are "fast progressors" whose core grows quickly, while others, with good collaterals, remain salvageable for hours.

This variability explains why treatment decisions have shifted from fixed clock limits towards imaging-based selection. Intravenous thrombolysis with recombinant tissue plasminogen activator has conventionally been given within 4.5 hours of onset, and mechanical thrombectomy, which removes a clot from a large cerebral artery by catheter, was for many years limited to about 6 hours. Trials using CT or MRI perfusion and diffusion imaging, including DEFUSE 3 and DAWN, showed benefit from thrombectomy up to 16 and 24 hours after last known well in carefully selected patients with a mismatch between core size and clinical deficit. Observational analyses have also described a strong time gradient: earlier reperfusion is associated with better neurological recovery and fewer complications. Because the clinical benefit of each minute is so large, prehospital triage, rapid imaging, and access to thrombectomy-capable centres are central to acute care. Reperfusion itself can injure tissue, and inflammation in the penumbra is an active target of research.

Long-term disability, cognition, and global burden

Survival after stroke is only part of the picture. Many survivors have persistent motor weakness, aphasia, dysphagia, sensory loss, fatigue, and depression, and these deficits limit employment, independence, and quality of life. Cognitive impairment is common after stroke, and stroke is among the most important modifiable contributors to dementia; a single stroke can unmask or accelerate decline in people with underlying small-vessel disease. Rehabilitation, secondary prevention with antithrombotic therapy and blood pressure control, and early specialist stroke-unit care all influence how much function is recovered.

At population level, the Global Burden of Disease 2023 analysis found that age-standardized incidence, mortality, and disability-adjusted life-year rates fell substantially since 1990, while the absolute number of strokes, deaths, and DALYs rose, driven by population growth and ageing. More than 80% of stroke deaths and DALYs now occur in low- and middle-income countries. Stroke remains the second leading cause of death worldwide and the third leading cause of death and disability combined. Within that burden, DALYs from ICH are proportionally larger than those from ischemic stroke, reflecting the young age and severity of many hemorrhages. Global figures in this area differ among sources because of differences in modelling, so comparisons across estimates should be made with care.

Hypertension

Definition

Hypertension is a sustained rise in arterial blood pressure. For adults, the WHO's clinical threshold is a systolic reading of at least 140 mmHg, a diastolic reading of at least 90 mmHg, or both, found on two different days WHO defines clinical hypertension in adults as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg on two different days. Risk does not switch on at a single line. High blood pressure can raise the risk of heart and kidney disease even below this threshold. For example, a systolic reading under 130 mmHg, though not classed as hypertension, still adds risk.

Primary and secondary hypertension

Clinicians divide cases by cause. Primary, or essential, hypertension has no single identifiable trigger. It reflects the accumulation of age, genetic, dietary, body-weight and metabolic influences, and it accounts for most adult cases. Most patients with hypertension have no clear etiology and are classified as having primary hypertension. Secondary hypertension is traced to a specific disorder that may be correctable. Between 5% and 10% of hypertensive patients may have secondary hypertension, which indicates an underlying and potentially reversible cause. Systematic screening suggests this proportion may be higher. In a 2024 study of 2,090 young adults with confirmed hypertension, secondary causes were identified in 29.6%. In that cohort, primary aldosteronism was the most common etiology (54.8% of secondary causes), followed by renovascular hypertension (18.4%), primary kidney disease (12.9%), drug-induced hypertension (6.0%), and pheochromocytoma and paraganglioma (5.9%).

The likely cause also varies with age. In children younger than 12 years, secondary causes account for 70% to 85% of hypertension cases, predominantly renal parenchymal disease. In older adults, atherosclerotic renal artery stenosis, renal failure, and hypothyroidism are common causes. Identifying secondary causes matters because patients with primary aldosteronism experience a higher rate of cardiovascular events including stroke when compared to those with blood pressure matched essential hypertension. Broad testing of every patient is not justified, given cost, low yield and false-positive results, so testing is generally targeted to younger patients.

Damage to target organs

Sustained pressure injures the vasculature first. Its effects include reduced arterial compliance, atheromatous lesions in large arteries, and hypertrophy or remodelling of small arteries, changes thought to contribute to retinal, renal and cerebral lesions Vascular structural alterations include reduced compliance, the appearance of atheromatous lesions in the large arteries, and hypertrophy or remodelling of small artery walls, and may be involved in the onset of retinal, renal and brain lesions.

The heart responds by thickening its muscular wall. Left ventricular hypertrophy (LVH) initially lowers wall stress and is an adaptive response, but it can later impair cardiac function and lead to heart failure Although left ventricular hypertrophy is an initially useful and well tolerated adaptive mechanism because it tends to reduce wall stress, it may subsequently lead to impaired cardiac function and even heart failure. LVH carries independent prognostic weight. It is a major independent risk factor for not only CVD morbidity and mortality but also for all-cause mortality and neurological pathologies.

In the kidney, damage to small vessels and filtering units reduces the capacity to clear wastes, with albuminuria an early warning sign. The brain is also affected. In patients with established arterial disease, an increasing number of signs of target organ damage was associated with more progression of global brain atrophy and more rapid decline in memory performance. These associations were independent of blood pressure, antihypertensive treatment, and other confounders. Because organ injury can progress silently, guidelines recommend routinely assessing renal function, albuminuria, and left ventricular hypertrophy on electrocardiography when evaluating vascular risk.

Regulatory mechanisms

Arterial pressure is determined by cardiac output and total peripheral resistance, so hypertension arises when output rises, resistance increases, or both. Several systems act on these two variables. The renin–angiotensin–aldosterone system is central. When renal perfusion falls, the kidney releases renin, which initiates a cascade through angiotensin II. Angiotensin II constricts arterioles and stimulates aldosterone release, and aldosterone promotes sodium and water retention, expanding plasma volume. Drugs targeting this pathway help reverse cardiac remodelling. ACE-inhibitors and calcium entry blockers more effectively bring about the regression of left ventricular hypertrophy than several other agents.

Sympathetic overactivity raises heart rate and contractility, constricts resistance vessels, and stimulates renin release. Sodium handling is equally important. Normally, the kidney excretes more sodium as pressure rises, a relationship known as pressure natriuresis. In hypertension this curve shifts, so a higher pressure is needed to excrete the same sodium load, and salt-sensitive individuals are most affected. Dietary salt is among the modifiable factors that feed into this process. Behavioural and lifestyle-related factors can put people at a higher risk for developing high blood pressure. These factors include eating too much salt (sodium), being overweight and not getting enough exercise, as well as drinking too much alcohol and using tobacco.

Vascular stiffness closes the loop. Ageing and sustained pressure degrade elastin and increase collagen in the aortic wall. A stiffened aorta returns the pulse wave early, raising systolic pressure and widening pulse pressure. Carotid–femoral pulse wave velocity is used as a measure of this stiffness, and elevated carotid-femoral pulse wave velocity is among the markers of organ damage assessed in community cohorts.

Measurement, monitoring and burden

Diagnosis rests on repeated readings taken with a validated sphygmomanometer, an appropriately sized cuff, and a rested patient. Out-of-office methods, including home monitoring and 24-hour ambulatory monitoring, distinguish white-coat effects from sustained hypertension and detect masked hypertension. Guidelines set different thresholds for these averages than for clinic readings.

Hypertension is often symptomless. High blood pressure has no symptoms in most people. It is a "silent killer". When symptoms occur, they are typically headache, shortness of breath, dizziness, chest pain, palpitations of the heart and nose bleeds. Consequently, awareness depends on measurement. An estimated 1.4 billion adults aged 30–79 years worldwide had hypertension in 2024; this represents 33% of the population in this age range. An estimated 600 million adults with hypertension (44%) are unaware that they have the condition. Control is also limited: approximately 320 million adults with hypertension (23%) have it under control. The Lancet summary of the 2025 WHO report describes undiagnosed and uncontrolled hypertension as one of the most important preventable causes of heart attack, stroke, chronic kidney disease, and dementia. In global burden rankings, elevated systolic pressure has repeatedly ranked as the leading modifiable risk factor for death. Access to treatment is uneven, and only 28% of low-income countries report that all WHO-recommended hypertension medicines are generally available in pharmacies or primary care facilities.

Heart failure and arrhythmias

Heart failure as a syndrome

Heart failure is a clinical syndrome rather than one lesion. It is defined by symptoms and signs that arise when the ventricles cannot supply the body's needs at normal filling pressures. The ejection fraction (EF), the share of the left ventricle's end-diastolic volume ejected per beat, is the main way to sort patients. The 2021 European Society of Cardiology guidelines divided patients into three groups by left ventricular EF: preserved (≥50%), moderately reduced (41–49%), and reduced (≤40%).

Heart failure with reduced EF (HFrEF) usually follows a loss of contractile tissue, most often after a myocardial infarction, which weakens the pump. Heart failure with preserved EF (HFpEF) is different. Here the muscle contracts with near-normal force, but the ventricle is stiff. Stiffness in HFpEF arises from both myocardial fibrosis and reduced distensibility of cardiomyocytes and the myocardium. Stiffness impairs relaxation and filling, so filling pressures rise and congestion follows even though the EF looks normal. Roughly half of all patients with heart failure have an EF of 50% or more. HFpEF patients are more often obese, diabetic, hypertensive, and in atrial fibrillation than HFrEF patients, and they also show a higher prevalence of chronic kidney disease. Because the EF is measured by echocardiography or cardiac magnetic resonance, the boundary between groups depends partly on the method used.

Compensatory mechanisms and their decline

Early heart failure is initially compensated. Sympathetic activation raises heart rate and contractility and constricts peripheral vessels, which helps maintain blood pressure. The renin–angiotensin–aldosterone system promotes sodium and water retention and increases preload. The ventricle also dilates and hypertrophies, which temporarily increases stroke volume through the Frank–Starling mechanism.

Over time these responses become maladaptive. Persistently high catecholamine and angiotensin II levels drive cardiomyocyte death, interstitial fibrosis, and further chamber dilation. The walls thicken and stiffen, and the pump weakens further. The same pathways also make the heart more prone to arrhythmia, which is why drugs that block them, such as beta-blockers and angiotensin-converting enzyme inhibitors, are central to treatment.

Mechanisms of arrhythmia

Arrhythmias arise from three basic mechanisms: abnormal automaticity, triggered activity, and reentry. Each depends on the ion channels and currents that generate the cardiac action potential. The cell must reach a sufficiently negative membrane potential for sodium channels to recover, and abnormal calcium handling can generate spontaneous depolarizations. Delayed afterdepolarizations result from abnormal diastolic release of calcium from the sarcoplasmic reticulum, through ryanodine receptors that open in response to calcium entry.

Reentry needs an anatomical or functional substrate in which a wavefront can circulate, usually a zone of slow or blocked conduction. In atrial fibrillation, this is the dominant mechanism. Electrical remodeling is central: dysfunction of L-type calcium channels, fast sodium channels, and various potassium channels shortens the atrial effective refractory period and the action potential duration. Shortened refractoriness allows multiple wavelets to persist, and the arrhythmia then perpetuates itself. Triggers, often from the pulmonary veins, initiate the process, while fibrosis sustains it, particularly in patients with structural heart disease such as heart failure.

Ventricular tachycardia (VT) most often reflects a scar left by a prior infarct, which creates a reentrant circuit around non-conducting tissue. Acute coronary ischemia is the most common cause of ventricular fibrillation, while scar from an earlier infarct is the most common cause of sustained monomorphic VT. Some inherited syndromes arise without visible structural change and are caused by ion channel defects. In long QT syndrome, mutations in potassium or sodium channels prolong repolarization and can produce torsades de pointes.

Bradyarrhythmias result from failure of impulse generation or conduction. The sinoatrial node sets the heart rate through slow depolarization, and the atrioventricular node delays conduction to the ventricles. Fibrosis, ischaemia, ageing, and drugs can slow or block these tissues, leading to sinus node dysfunction or atrioventricular block that may require a pacemaker.

Why arrhythmia and heart failure coexist

The two conditions share causes, including coronary disease, cardiomyopathy, hypertension, and valve disease, and each worsens the other. Fibrosis and scarring that impair pumping also create the substrate for reentry. Neurohormonal activation, stretch of the chambers, and electrolyte disturbances lower the threshold for ectopy and sustained arrhythmia. In turn, atrial fibrillation removes the contribution of atrial contraction to filling, and prolonged rapid rhythms can weaken the ventricle further.

Sudden cardiac death

Sudden cardiac death (SCD) is most often caused by ventricular arrhythmia. Ventricular arrhythmias that precipitate cardiac arrest are the most common mechanism of sudden death. Coronary disease is the largest underlying cause, and coronary artery disease remains the leading cause of SCD, with up to 80% of patients affected. Reduced EF raises the risk further, and HFrEF is recognised as a high-risk population for sudden death. Antiarrhythmic drugs have limited value in this group, so implantable cardioverter-defibrillators are the main preventive strategy for patients with structural disease and reduced ventricular function.

Valvular, rheumatic, and congenital heart disease

Valve disorders: stenosis and regurgitation

Valve disease is usually described by the way a valve fails. In stenosis, the leaflets or the orifice are too narrow to let blood pass, so the chamber behind the valve must generate higher pressure to push blood forward. In regurgitation (also called insufficiency), the valve does not close fully, so blood leaks backward with each beat. The two often coexist, and a single valve can show both. The most common causes are degeneration, rheumatic injury, infection, and congenital malformation.

Calcific aortic valve disease illustrates how degeneration works. For decades it was regarded as passive wear and tear, but there is now compelling histopathologic and clinical data suggesting that calcific valve disease is an active and multifaceted condition, involving lipoprotein deposition, chronic inflammation, and the transformation of valve interstitial cells into bone-forming cells. The first phase, aortic sclerosis, thickens and mildly calcifies the valve without obstructing flow. Progression to stenosis matters because calcification is largely responsible for the hemodynamic progression of aortic stenosis. Its risk factors overlap with those of atherosclerosis: age, hyperlipidaemia, diabetes, hypertension, male sex and smoking. In patients younger than about 70 who need surgery, a congenitally bicuspid valve is the usual cause, whereas age-related degenerative calcification of a normal tricuspid valve is the primary cause in patients older than 70. Infective endocarditis, by contrast, destroys leaflet tissue and typically produces regurgitation.

Rheumatic heart disease

Acute rheumatic fever (ARF) is an immune reaction to a throat infection with group A streptococci. The mechanism is thought to involve molecular mimicry, in which antibodies raised against bacterial components cross-react with heart tissue, although the detailed mechanism is still debated. Repeated episodes of ARF, whether undetected, subclinical, or diagnosed, may progressively lead to RHD unless prevented by periodic penicillin. The valve injury is therefore cumulative, and the mitral valve is most often involved. Chronic RHD is defined by valve regurgitation and/or stenosis and can be complicated by arrhythmias, systemic embolism, infective endocarditis, pulmonary hypertension, heart failure and death.

Estimates of the burden have changed as screening has improved. Earlier Global Burden of Disease analyses reported 9 million disability-adjusted life years lost, 33 million prevalent cases and 275,000 deaths each year, with deaths occurring predominantly in low- and middle-income countries. A more recent systematic estimate states that in 2022, RHD affected over 55 million people worldwide, the majority in low- and middle-income countries. The disease is concentrated in disadvantaged populations: it predominantly affects children, adolescents, and young adults in LMICs, and it is particularly prevalent in Africa and the Pacific region. Underreporting is widespread because of the scarcity of comprehensive disease registries, the reliance on passive surveillance systems, and the underreporting of both acute and chronic cases. The gap is not a matter of medical knowledge alone. Primary prevention (treating streptococcal pharyngitis) and secondary prevention (penicillin prophylaxis after an attack) are available and cost-effective, which explains why ARF and RHD are rare in the developed world.

Congenital heart disease

Congenital heart disease (CHD) is the most common congenital malformation and occurs in 1% of all live births. The common forms include ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot, coarctation of the aorta, and hypoplastic left heart syndrome. Severe lesions are usually recognised in the neonatal period or infancy, through fetal ultrasonography, pulse oximetry, or clinical signs in the first weeks of life. Treatment has been transformed by surgery and catheter-based interventions. In the United States, one-year survival for high-complexity defects was about 20% in 1940–1959 but reached about 85% in the 1980s, and the currently accepted survival rate is more than 90% for most CHDs.

Adults living with repaired defects

Because so many children now survive, the adult population with CHD has grown quickly. By 2010 the number of adults aged 20–64 with recalled CHD had risen by a factor of 2.3 to 273,000, and an estimated 510,000 are projected for 2050. Other estimates, based on different methods, are considerably higher, so the figures should be read as approximate. Repair, however, is rarely curative. Surgically corrected patients carry a continuing risk of arrhythmia, valve dysfunction, heart failure, and reoperation, and the outcome depends strongly on the lesion. Patients with moderate or severe CHD still have a reduced life span, whereas survival of patients with most mild CHD is similar to the general population. Patients with Eisenmenger syndrome, the Fontan circulation, and complex lesions have the poorest long-term outlook. A further challenge is organisational. A 2013 United States survey found that the majority of adults with CHD, even of moderate or severe complexity, were managed by general cardiologists, and referral to specialised adult congenital care has been associated with lower mortality. Lifelong follow-up, including planning for pregnancy and later-life complications, has therefore become a core part of cardiology practice.

Peripheral arterial and venous disease

Peripheral arterial disease

Peripheral arterial disease (PAD) is most often caused by atherosclerosis in the arteries that supply the legs, although the arms can also be affected. Plaque narrows or occludes these vessels, so tissue beyond the lesion receives less oxygen than it needs. Less common causes include coarctation of the aorta, thromboangiitis obliterans (Buerger's disease), and other forms of vasculitis.

Symptoms depend on the severity and location of the blockage. The classic symptom, intermittent claudication, is an ache, cramp or sense of heaviness in the calf, thigh or buttock that appears predictably during walking and eases within minutes of rest. During exercise the working muscle demands more oxygen than the stenosed artery can supply, the pressure gradient across the lesion increases, and local vessels dilate, which further reduces perfusion. Symptoms generally do not appear until the lumen has narrowed by about 50 to 70 percent. As disease advances, pain begins at rest, usually in the forefoot, and non-healing ulcers, gangrene and critical limb ischaemia may follow. A sudden, complete arterial occlusion in a limb is an emergency, marked by severe pain, pallor and loss of the pulse below the blockage.

A substantial minority of patients have no symptoms at all, and a further group has atypical complaints such as joint pain or reduced exercise tolerance, so PAD is often underdiagnosed. Because it shares risk factors with coronary and cerebrovascular disease, including smoking, diabetes and dyslipidaemia, it is regarded as a marker of systemic atherosclerosis. Patients with PAD carry a markedly higher risk of death from heart attack and stroke than people without it, which is why leg symptoms prompt assessment of the whole vascular tree.

Venous thromboembolism

Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT), usually in the leg, and pulmonary embolism (PE), in which fragments of thrombus lodge in the pulmonary arteries. Venous thrombi are composed mainly of red cells and fibrin, with a relatively small platelet component, and they are loosely attached to the vessel wall, which makes them prone to detaching and embolising. Many DVTs are clinically silent, and an estimated incidence of about 1 per 1,000 people per year is often quoted for VTE overall.

The mechanisms of venous thrombosis are usually summarised by Virchow's triad: venous stasis, hypercoagulability and endothelial injury. Rudolf Virchow described the link between venous thrombi and pulmonary embolism in 1856, but the three-part framework was consolidated only decades later. Stasis is often regarded as the most consequential factor, yet it rarely produces thrombosis alone; the risk rises sharply when stasis coincides with vascular injury or a hypercoagulable state. Common clinical risk factors map onto these elements, including surgery, trauma, malignancy, prolonged immobility, pregnancy, heart failure, varicose veins, obesity, advanced age and previous DVT. Treatment centres on anticoagulation, with thrombolysis or mechanical removal reserved for severe cases.

Chronic venous insufficiency and varicose veins

Leg veins return blood against gravity, relying on the calf muscle pump and a series of one-way valves. When valves are damaged, most often after a DVT, or are weakened by inherited vein-wall abnormalities, blood flows backwards and pools in the lower limb, raising venous pressure, particularly during prolonged standing. The resulting venous hypertension produces dilated, tortuous superficial veins (varicose veins), ankle oedema, skin pigmentation, eczema and, in some patients, venous leg ulcers near the inner ankle. Post-thrombotic syndrome is a related complication of earlier DVT. Management includes graduated compression stockings, leg elevation, exercise and, for symptomatic reflux, endovenous ablation or surgical removal of the affected veins.

Aortic aneurysm and dissection

An aortic aneurysm is a permanent, localised dilatation of the aorta; the abdominal segment is the most frequently affected. Abdominal aortic aneurysm (AAA) is commonly defined as a dilatation exceeding about 1.5 times the normal diameter, and it is most common in older men, smokers and people with hypertension. Most AAAs are silent and found incidentally on ultrasound or CT imaging. They enlarge gradually, and rupture occurs when the mechanical stress on the wall exceeds its strength. Rupture classically presents with sudden back or abdominal pain, a pulsatile mass and hypotension or shock, and it is a major cause of death. Elective repair is generally offered when the aneurysm reaches about 5.5 cm in men or 5 cm in women, or when it expands rapidly, using open surgery or endovascular stent grafting.

Aortic dissection occurs when blood enters a tear in the aortic wall and separates its layers, creating a false lumen that can compromise branch vessels and limb perfusion. It typically causes abrupt, severe tearing pain and carries a worse prognosis than uncomplicated aneurysm. Because both aneurysm and dissection often produce no warning symptoms until a catastrophic event occurs, screening and imaging of at-risk individuals are central to prevention.

Risk factors and risk assessment

Modifiable risk factors

Cardiovascular disease rarely has a single cause. The INTERHEART case-control study, which compared people with a first myocardial infarction with matched controls in 52 countries, is the largest guide to this question. Its nine modifiable exposures, including smoking, an elevated apolipoprotein B to apolipoprotein A1 ratio, hypertension, diabetes, abdominal obesity, psychosocial stress, low daily fruit and vegetable intake, and physical inactivity, accounted for about 90% of the population attributable risk in men and 94% in women. The individual odds ratios were highest for the lipid ratio (top quintile about 3.25), smoking (about 2.87) and psychosocial stress (about 2.67), with diabetes (about 2.37) and hypertension (about 1.91) also strongly associated. Regular alcohol use showed only a weak association in this sample, so the "harmful use" category used in public health guidance is not captured by the study's findings.

These factors cluster rather than act alone. Abdominal obesity, insulin resistance, dyslipidaemia and high blood pressure often occur together, so their effects overlap, and a person with several exposures carries more risk than the sum of single-factor estimates would suggest. Population attributable risk is also shaped by prevalence: a common exposure with a modest effect can account for more cases than a rare exposure with a large one. This is why tobacco, blood pressure and lipids dominate population estimates even though their individual effects differ.

Non-modifiable factors

Age is the strongest non-modifiable determinant, and risk rises steeply with each decade. Sex also shapes baseline risk. In the INTERHEART analysis, women had their first myocardial infarction on average about nine years later than men, and this gap was largely explained by higher risk-factor levels at younger ages in men, rather than by sex alone. Family history increases risk through shared genes and shared household environments, and a strong family history of early disease can indicate a monogenic disorder. Ethnicity matters because risk-factor profiles and their age patterns differ between groups; in INTERHEART, South Asian participants carried more risk factors at ages under 60. Such differences reflect both genetic background and social exposures, and they should not be read as fixed biological categories.

Multifactorial risk assessment and prediction equations

Clinical guidelines estimate absolute risk, usually the probability of a cardiovascular event over 10 years, by combining age, sex, blood pressure, lipids, diabetes, smoking status and other variables into a risk prediction equation. Such tools are used to decide whether to start preventive drugs, especially statins and antihypertensives, in people without established disease. The American Heart Association's 2023 PREVENT equations are sex-specific, exclude race as a predictor, and estimate 10- and 30-year risk for total cardiovascular disease, atherosclerotic disease and heart failure in adults aged 30 to 79. They can incorporate kidney function, body mass index and a neighbourhood-level social deprivation index.

Two properties determine whether a model is trustworthy. Discrimination describes how well it ranks people who will and will not have an event, and calibration describes whether predicted risks match observed event rates. Earlier pooled cohort equations were poorly calibrated in contemporary populations, overestimating risk by roughly half in one validation, whereas PREVENT's calibration slope was close to 1. Calibration is not guaranteed in new settings, however. A 2025 study across four US academic health systems found that PREVENT's calibration varied considerably between sites and across sociodemographic and cardiometabolic subgroups, even though its discrimination was moderate. Models also omit factors such as lipoprotein(a) and detailed social circumstances, and their thresholds (for example, low under 5%, high at 20% or more) are policy choices as much as biological ones.

Environmental and psychosocial exposures

Long-term exposure to fine particulate matter (PM2.5) and nitrogen dioxide is consistently linked with coronary heart disease and stroke. An umbrella review of systematic reviews found the strongest evidence for ischaemic heart disease, stroke and cardiovascular mortality, with stronger associations in some Asian countries and among older people and those with existing heart disease. Proposed mechanisms include autonomic instability, endothelial dysfunction, oxidative stress and inflammation. Short-term studies have produced mixed results, which makes the long-term exposure data more consistent.

Transport noise is an increasingly studied exposure. A 2023 umbrella review estimated that every 10 dB(A) increase in road noise was associated with higher risks of ischaemic heart disease, stroke and heart failure, while the cohort AIRCARD reported that road traffic noise predicted cardiovascular disease and all-cause mortality independently of air pollution. Suggested pathways include sleep disruption, stress-hormone release, sympathetic activation and vasoconstriction. Evidence for noise is less extensive than for air pollution, and because traffic-derived exposure models share inputs for both pollutants, separating their effects is difficult.

Psychosocial stress is part of the same picture. In INTERHEART, a composite of depression, global stress, financial strain, low sense of control and life events such as job loss or family conflict was strongly associated with first myocardial infarction. These exposures are unevenly distributed by income and neighbourhood, so they overlap with the social determinants of health and with confounding by lifestyle, which complicates any attempt to attribute disease to one exposure.

Genetics and molecular mechanisms

Monogenic disorders and the LDL receptor pathway

Familial hypercholesterolaemia (FH) shows how a single gene can reshape an individual's whole cardiovascular risk. Most cases arise when the liver cannot take up and degrade LDL, usually because of a loss-of-function change in the LDL-receptor gene, although variants in the APOB gene, which encodes apolipoprotein B, cause a similar defect. Inheritance is mainly autosomal dominant, and the number of defective copies matters, so people with two faulty copies have far higher LDL levels than heterozygotes. A rare recessive form involves LDLRAP1, a protein needed for the receptor to be internalised by liver cells. Heterozygous FH is estimated at about 1 in 250 to 300 people in the general population.

PCSK9 sits upstream of this pathway. Surface LDL receptor numbers depend on PCSK9, which steers the receptor toward lysosomal breakdown, so fewer receptors remain available to clear circulating LDL. Gain-of-function mutations in PCSK9 cause autosomal dominant hypercholesterolemia, while loss-of-function mutations are associated with reduced plasma LDL-C. This genetic evidence informed drug development. Antibodies such as evolocumab and alirocumab block the PCSK9–receptor interaction, and inclisiran blocks PCSK9 production using small interfering RNA. Some studies also suggest PCSK9 acts on the vessel wall independently of its effect on LDL. PCSK9 induces the expression of pro-inflammatory cytokines and contributes to inflammation within the vascular wall. How much of its harm is LDL-independent is not yet fully understood.

Genome-wide association studies and polygenic scores

The first genome-wide association study (GWAS) of coronary artery disease, published in 2007, identified a locus at 9p21 that raised risk by roughly 25 to 30% per risk allele. Discovery analyses over the following years identified 163 common genetic loci associated with CAD at genome-wide significance. Most of these signals involve common variants, and many of these loci map to genes involved in blood pressure regulation, lipid metabolism, inflammation, vascular remodelling, and nitric oxide signalling.

A polygenic risk score (PRS) condenses these many small effects into one value. It is a method of aggregating an individual's genetic information, weighted by associations between genetic variants and disease outcomes identified from GWAS. Early scores used only a few variants, whereas newer genome-wide scores incorporate far more. One multi-ancestry score, GPS_Mult, drew on more than 269,000 cases across five ancestries. In UK Biobank participants of European ancestry it had an odds ratio of 2.14 per standard deviation, and after adjusting for correlated clinical risk factors including blood pressure, LDL cholesterol, diabetes and body mass index, this risk estimate was only modestly attenuated. Predictive performance is weaker in people of non-European ancestry. Score performance remains considerably lower than the theoretical maximum, particularly among individuals of non-European ancestry. Clinical value is still being tested. In secondary analyses of statin trials, a 27-variant CAD genetic risk score identified individuals at elevated risk of recurrent events.

Inflammatory pathways

Inflammation links genetic susceptibility to the arterial wall. Macrophages that engulf oxidised LDL within the intima release cytokines such as interleukin-1β and interleukin-6, which recruit further leukocytes and sustain plaque growth. The liver responds to interleukin-6 by producing C-reactive protein (CRP), and high-sensitivity CRP is widely used as a biomarker of cardiovascular risk. Whether inflammation is a cause rather than a bystander has been tested directly. The CANTOS trial gave canakinumab, an antibody against interleukin-1β, to patients with prior myocardial infarction and raised CRP. It reduced recurrent cardiovascular events without lowering LDL cholesterol, but increased fatal infections. Colchicine trials, notably LoDoCo2, reported fewer events in chronic coronary disease. Mendelian randomisation studies of CRP-raising genetic variants have generally not supported CRP itself as causal, so CRP may be a marker of inflammatory activity rather than its driver.

Gene–environment interaction and hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common inherited heart muscle disease, affecting roughly 1 in 200 to 500 people. Two sarcomere proteins, myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7), are involved in about 70% of sarcomere gene mutation-positive HCM. MYBPC3 variants are the more common cause overall, and many are truncating. Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome events, leading to allelic imbalance and haploinsufficiency. MYH7 variants typically act through the myosin motor itself. Biophysical analyses indicate that HCM mutations in β-myosin heavy chain increase ATPase activity, actin-sliding velocity, and power.

Genotype shapes the clinical course. MYH7 mutations are associated with an earlier onset of symptoms, more pronounced hypertrophy, and poor prognosis. By contrast, MYBPC3 mutations more commonly predispose to progressive systolic dysfunction and heart failure. Penetrance is also incomplete and age-dependent. HCM has been considered a heterogeneous cardiac disease with incomplete penetrance and variable phenotypic presentation, age of onset and severity. Environmental factors modify the outcome: aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations. The same variant can therefore produce different disease in different people, depending on age, other genetic variation and exposures.

Global burden and epidemiology

Current burden

Cardiovascular disease (CVD) is the largest single cause of death in the world. The World Health Organization (WHO) estimates that 19.8 million people died from CVD in 2022, about 32% of all deaths that year, and approximately 32% of all global deaths. Heart attacks and strokes account for more than four in five of these deaths, and roughly a third of CVD deaths occur in people under 70 one third of these deaths occur prematurely in people under 70 years of age. Among the premature deaths from noncommunicable diseases recorded in 2021, CVD's share was at least 38% at least 38% were caused by CVDs.

Long-term trends

In absolute terms, the toll has risen steadily. A 2023 analysis in the Journal of the American College of Cardiology reports global death counts due to CVD increased from 12.4 million in 1990 to 19.8 million in 2022, a change it links to population growth, ageing and preventable metabolic, behavioural and environmental risks. Rates adjusted for age tell a more favourable story. The World Heart Federation notes that the age-standardised rate fell from 354 to 239 per 100,000 between 2000 and 2019 the age-standardized rate has dropped significantly (from 354 per 100,000 population in 2000 to 239 in 2019). The decline is not uniform: between 2015 and 2022, age-standardised CVD mortality rose in 27 locations even the age-standardized CVD mortality increased in 27 locations. In high-income regions the fall has been steepest; the Global Burden of Disease (GBD) 2017 analysis found that the age-standardised death rate in high socio-demographic index regions fell by more than half between 1990 and 2017 The ASDR of CVD in high SDI regions decreased more than 50% from 1990 to 2017.

Regional and income patterns

The burden falls heavily on poorer countries. Over three quarters of CVD deaths take place in low- and middle-income countries. Using GBD 2020 estimates, the highest CVD mortality rates were in Eastern Europe and Central Asia, with elevated rates also in Oceania, North Africa and the Middle East, sub-Saharan Africa, and South and Southeast Asia, while the lowest were in high-income Asia Pacific, North America, Latin America, Western Europe and Australasia The highest mortality rates attributable to CVD in 2020 were in Eastern Europe and Central Asia, with higher levels also seen in Oceania, North Africa and the Middle East, Central Europe, sub-Saharan Africa, and South and Southeast Asia. Rates were lowest for locations in high-income Asia Pacific and North America, Latin America, Western Europe, and Australasia.

The cause mix also varies by setting. Ischaemic heart disease and stroke together make up 85% of the age-standardised death rate for CVD Ischemic heart disease and stroke accounted for 85% of the total age-standardized death rate (ASDR) of CVD.. Haemorrhagic subtypes show their own geography: the prevalence of intracerebral haemorrhage is highest in Oceania, western sub-Saharan Africa and Southeast Asia, while subarachnoid haemorrhage is highest in Japan and the Andean region of Latin America Age-standardized prevalence of intracerebral hemorrhage was highest in Oceania, western sub-Saharan Africa, and Southeast Asia. Age-standardized prevalence of subarachnoid hemorrhage was highest in Japan and Andean Latin America.. Within countries, sex differences in cause are also marked. In Chile, stroke predominates among women and ischaemic heart disease among men Stroke predominated in females and ischaemic heart disease in males., and across the GBD 2017 data, age-standardised CVD death and DALY rates in men were about 1.5 times those in women The ASDR and age-standardized DALYs rate (ASYR) of CVD were 1.5 times greater in men compared with women.

Measuring the broader burden

Death counts understate the problem because they do not capture years lived with illness. Disability-adjusted life years (DALYs) address this by adding together the sum of YLLs and YLDs, where YLL is years of life lost to premature death and YLD is years lived with disability. Disability weights are derived from population surveys, so they reflect how a health state affects people in general These disability weights were constructed from surveys of the general population to reflect the impact of the health state on the population.. On this measure, there were 437 million CVD DALYs globally in 2023, a 1.4-fold increase from the number in 1990 of 320 million. CVD ranks as the leading cause of DALYs, representing 15.6% of all disease burden in 2023. Disability is a particularly large part of the picture: years lived with disability from CVD doubled from 17.7 million to 34.4 million between 1990 and 2019. Stroke alone accounted for 157 million DALYs in 2023 for stroke globally, and ischaemic heart disease and stroke were the two largest sources of cardiovascular DALYs, at 193 and 157 million respectively the two leading causes of cardiovascular DALYs (193 and 157 million, respectively). Heart failure also drives long-term disability, but it is not broken out separately in these headline figures.

Cause-of-death statistics depend on coding conventions. The WHO Mortality Database assigns one underlying cause from death certificates, and only countries in which at least 65% of deaths are registered are included This data comes from the World Health Organization (WHO)'s Mortality Database, which compiles deaths reported by each country annually, based on the underlying cause of death listed on death certificates.. For countries with weaker registration, the GBD and WHO Global Health Estimates rely on verbal autopsies and statistical modelling to assign causes These estimates assign each death a single cause based on data on the underlying cause of death listed on death certificates, verbal autopsies, and statistical modeling.. Because estimates of this kind are sensitive to these assumptions, comparisons between countries and across years should be read with that uncertainty in mind.

Diagnosis and clinical assessment

Clinical evaluation

Patients with cardiovascular disease usually present with chest discomfort, breathlessness, palpitations, faintness, leg swelling or, in the most serious cases, collapse. The history carries the most diagnostic weight. For chest pain, clinicians ask about location, quality, triggers such as exertion, duration, and whether rest or nitrates relieve it. Pressure-like pain brought on by effort and eased by rest points toward angina, whereas sharp, positional or reproducible pain makes it less likely. Breathlessness requires questions about orthopnoea, paroxysmal nocturnal dyspnoea and exercise tolerance, which suggest left-sided heart failure. Pleuritic pain or sudden breathlessness raises the possibility of pulmonary embolism or aortic dissection.

The examination looks for a raised jugular venous pressure, a displaced or heaving apex beat, additional heart sounds, murmurs that change with posture or manoeuvres, basal crackles, peripheral oedema, and pulse or blood pressure differences between the arms. These findings are combined with a pre-test estimate of probability, which shapes how far the investigation proceeds.

Electrocardiogram and biomarkers

The 12-lead electrocardiogram is the cheapest and fastest first test. It can show ischaemic ST-segment changes, arrhythmias, conduction defects and Q waves from an old infarct, and it is repeated whenever symptoms change. A normal tracing does not exclude coronary disease or an acute infarct, so it is never used alone.

Cardiac troponin I and T are the main biomarkers of myocardial injury. High-sensitivity assays, first introduced across Europe and Australasia in 2010, detect concentrations far below older thresholds. In patients with suspected acute coronary syndrome and a non-ischaemic ECG, a high-sensitivity troponin below 5 ng/L gives very high negative predictive value and sensitivity, missing as few as 1 in every 200 patients tested. Guidelines nonetheless still recommend serial sampling, because troponin concentrations on presentation were within the normal reference range in up to one-fifth of patients who would subsequently be diagnosed with acute myocardial infarction on repeat sampling. Pathway trials support a cautious early rule-out: the HiSTORIC cluster trial found that its early pathway reduced length of stay and hospital admission without increasing adverse cardiac events.

Natriuretic peptides (BNP and NT-proBNP) are released mainly by stretched ventricular myocytes, so their levels track wall stress and filling pressure. A low value makes heart failure an unlikely cause of breathlessness. A raised value needs interpretation, since age, renal impairment and atrial fibrillation raise it, while obesity lowers it. Sacubitril–valsartan also raises BNP, which is why NT-proBNP is often preferred in treated patients.

Echocardiography and other imaging

Transthoracic echocardiography is the first-line imaging test for cardiac structure and function. It estimates ejection fraction, chamber size, wall thickness, valve performance and pulmonary pressure, and it is portable, radiation-free and repeatable. Its limitations are image quality, which depends on body habitus, lung disease and operator skill, and its poor view of the coronary arteries. Transoesophageal echocardiography gives a closer view of the left atrium and the valves.

Coronary CT angiography images the coronary tree non-invasively. In the ACCURACY trial, 64-multidetector row CCTA had a sensitivity of 95% and NPV of 99% to detect more than 50% stenosis. In the DISCHARGE trial, CT was an accurate, noninvasive alternative to invasive coronary angiography in patients with stable chest pain and intermediate pretest probability. In SCOT-HEART, CCTA led to a change in diagnosis in 27% of patients, a change in investigations in 15% of patients, and a change in treatment in 23% of patients. Its limits include calcified or stented vessels, irregular or fast heart rates, iodinated contrast, and radiation dose. A narrowed lumen on CT also says nothing by itself about whether that lesion causes ischaemia. Its value in acute chest pain is more contested: in ROMICAT-II, results were achieved without greater risk for undetected acute coronary syndromes and without an increase in the cost of care, but increased diagnostic testing and radiation exposure were observed in the CCTA group.

Cardiac magnetic resonance imaging characterises tissue rather than only anatomy. It can show myocardial oedema, scar on late gadolinium enhancement, stress-induced perfusion defects and infiltrative disease, without ionising radiation. Scans are long, some implanted devices exclude patients, and gadolinium agents require caution in renal impairment.

Invasive coronary angiography, a contrast X-ray of the coronary arteries, remains the reference standard for luminal anatomy and allows treatment in the same session. It is invasive, carries risks of bleeding, contrast-related kidney injury and arterial injury, and it does not reveal plaque composition or whether a lesion limits flow.

Functional testing and fractional flow reserve

Anatomy alone can mislead, because a severe-looking stenosis may not restrict blood flow, while a moderate one may. Stress testing, using exercise ECG, stress echocardiography, nuclear or PET perfusion imaging, or stress CMR, provokes ischaemia to show its functional effect, though interpretation is limited when the resting ECG is abnormal or the patient cannot exercise.

Fractional flow reserve (FFR) measures the pressure beyond a stenosis, relative to the aortic pressure, under maximal hyperaemia, using a pressure wire during catheterisation. Compared with angiography alone, FFR is more effective at selecting lesions associated with myocardial ischaemia and impaired outcomes, and deferring intervention on lesions without ischaemic FFR values has proven safe. A value of 0.80 or less is conventionally taken as ischaemic. In FAME 2, the rate of the primary end point was significantly lower in the PCI group than in the medical-therapy group (8.1% vs. 19.5%), a difference driven by a lower rate of urgent revascularization. Many lesions planned for treatment on angiography alone were not ischaemic: more than 25% of patients with stable coronary artery disease who were scheduled to undergo PCI on the basis of clinical and angiographic data had no stenosis with an FFR value of 0.80 or less. The evidence is not uniformly favourable, however. In FAME 3, the 1-year incidence of the composite primary end point was 10.6% among patients randomly assigned to undergo FFR-guided PCI and 6.9% among those assigned to undergo CABG in three-vessel disease. Physiology-guided strategies have therefore been described as having conflicting results compared with non-physiology-guided revascularisation. FFR can also be estimated from CCTA data; an expert consensus concluded that a reasonably strong body of evidence supports the use of CT-FFR for the diagnosis of CAD in patients presenting with stable chest pain syndromes and this results in diagnostic rates comparable to invasive FFR.

Prevention and treatment

Prevention

Prevention is usually split into primary prevention, which aims to stop disease in people who have risk factors but no clinical events, and secondary prevention, which aims to stop recurrence in people who already have established disease. The same tools apply to both, but secondary prevention yields a larger absolute benefit because the baseline risk is higher. Lifestyle change is the foundation: stopping smoking, eating more vegetables, whole grains, legumes, and unsaturated fats while cutting salt and processed meat, doing regular aerobic activity, and keeping a healthy weight. Blood pressure control is among the most effective measures. The SPRINT trial (2015) found that an intensive systolic target below 120 mmHg reduced cardiovascular events and all-cause death compared with a target below 140 mmHg, and current guidelines individualise targets rather than applying one threshold to everyone.

Lowering LDL cholesterol is the other central strategy. A Cholesterol Treatment Trialists' Collaboration analysis of statin trials found that each 1 mmol/L reduction in LDL cholesterol was associated with roughly a one-fifth reduction in major vascular events, and that more intensive regimens produced further reductions. A later meta-analysis of 60 randomised trials of guideline-recommended LDL-lowering drugs, including ezetimibe and PCSK9 inhibitors, estimated a hazard ratio of about 0.78 per 1 mmol/L, with a slightly larger effect in primary prevention (0.74) than in secondary prevention (0.80). Non-statin agents are usually added when LDL remains high on statins or when statins cannot be tolerated. Aspirin for primary prevention, once widely used, is now restricted in most guidelines because bleeding risk can outweigh benefit in people without established disease.

Drug classes

Antiplatelet agents, mainly aspirin and P2Y12 inhibitors such as clopidogrel and ticagrelor, reduce platelet aggregation. They are central to acute coronary syndromes and to the period after stent placement, often as combined therapy for a defined duration. Anticoagulants, including warfarin and direct oral anticoagulants, are used to prevent embolic stroke in atrial fibrillation and to treat venous thromboembolism. Beta-blockers lower heart rate and myocardial oxygen demand and are used after infarction and in heart failure with reduced ejection fraction. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists are the other core heart-failure drugs.

Sodium–glucose cotransporter-2 (SGLT2) inhibitors, such as dapagliflozin and empagliflozin, illustrate how a drug developed for diabetes became a heart-failure therapy. Their benefit does not depend on glucose lowering alone; they produce glycosuria, mild diuresis, and reduced preload and afterload. The 2021 European Society of Cardiology guidelines recommended them as first-line therapy for heart failure with reduced ejection fraction, and later updates extended the recommendation across the ejection-fraction range. The ACC/AHA/HFSA guideline gives a Class 1 recommendation for reduced ejection fraction and Class 2a for mildly reduced and preserved ejection fraction. Trial analyses suggest benefit wanes soon after discontinuation, so persistence is generally advised.

Revascularisation: PCI or CABG

Percutaneous coronary intervention (PCI) opens a narrowed artery with a balloon and usually leaves a stent, using a catheter inserted through a peripheral artery. Coronary artery bypass grafting (CABG) creates detours around the obstruction, typically using saphenous vein or internal mammary artery. Choice depends on anatomy (number of diseased vessels, left main involvement, complexity scores), diabetes, left ventricular function, and patient preference, and is typically made by a multidisciplinary "heart team". For multivessel disease, older trials and a broad review favoured CABG for survival, reduced myocardial infarction, and fewer repeat procedures, and the advantage was greatest in diabetes and ischaemic cardiomyopathy. However, the BEST trial, with 11.8 years of median follow-up, found no significant difference in major adverse cardiac events between everolimus-eluting stents and CABG. For left main disease, PCI may achieve outcomes similar to CABG in patients with low or intermediate SYNTAX scores. Observational Medicare data (2018–2023) favoured CABG for stable multivessel disease, and the evidence base remains debated, particularly around guideline recommendation classes.

Devices, valves, and rehabilitation

Implantable cardioverter-defibrillators are used for primary prevention of sudden cardiac death in selected patients with reduced ejection fraction, while pacemakers treat symptomatic bradycardia and conduction block. Cardiac resynchronisation therapy addresses ventricular dyssynchrony in some heart-failure patients. For severe aortic stenosis, surgical valve replacement has been joined by transcatheter aortic valve implantation, which has been extended from older, high-risk patients to lower-risk groups. Transcatheter repair and replacement are also used for mitral regurgitation in selected cases. Cardiac rehabilitation, combining supervised exercise, education, risk-factor management, and psychological support, reduces hospital readmission and improves functional capacity after infarction, heart surgery, and heart failure.

Public health policy and health systems

Global targets

Cardiovascular disease is central to the global noncommunicable disease (NCD) agenda. Under the 2030 Agenda, the target is to reduce the probability of death from any of the four main NCDs between ages 30 and 70 by one third by 2030. Cardiovascular disease is the largest part of this goal: it is the leading cause among the four targeted causes and accounts for half of deaths in this age group. Earlier, in 2011, all 194 member states of the World Health Assembly agreed to adopt the first global NCD target, a 25% reduction in premature mortality from NCDs by 2025.

Progress has lagged. A 2024 review by Mendis and Graham concluded that global progress in addressing cardiovascular diseases has been insufficient to attain the nine WHO NCD targets and the SDG target, and that progress has been slowest in low- and middle-income countries. Analyses of what the target requires point to seven accelerating interventions, spanning tobacco control, treatment to reduce cardiovascular risk, dietary sodium reduction, household air pollution, elimination of artificial trans fat, reduced alcohol use, and cancer prevention and treatment.

Population-level measures

Population-level measures aim to change the environments in which risk accumulates, rather than relying only on individual treatment. Tobacco control is the most established example. Dietary salt is another: WHO recommends that adults consume less than 5 g of salt per day, and reducing intake lowers blood pressure across the population. WHO's REPLACE package, introduced in 2018, sets out a route to eliminating industrially produced trans fat, which raises LDL cholesterol. Front-of-pack warning labels have been most studied in Chile, where a 2016 law introduced black warning symbols; evaluations reported reduced purchases of labelled high-sugar and high-salt products.

Fiscal measures are gaining prominence. In July 2025, WHO launched the "3 by 35" Initiative, urging countries to raise real prices on tobacco, alcohol, and sugary drinks by at least 50% by 2035 through health taxes. The initiative also estimates that taxes on these products could generate about $1 trillion in health revenue by 2035. Implementation is contested: many countries continue to provide tax incentives to unhealthy industries, including tobacco, and long-term investment agreements with industry that restrict tobacco tax increases can further undermine national health goals.

The HEARTS approach in primary care

Most people with cardiovascular risk are first seen in primary care, and the HEARTS technical package is WHO's response to that setting. It supports ministries of health in strengthening CVD management in primary health care settings. Its six modules cover healthy-lifestyle counselling, evidence-based treatment protocols, access to essential medicines and technology, risk-based management, team-based care, and monitoring systems. Hypertension serves as the clinical entry point, because it drives much of the disease and is the easiest risk factor to detect and treat at this level. The programme has been implemented in over 40 countries, and it incorporates the recommendations of the WHO 2021 hypertension treatment guideline.

Drug availability and task-sharing are central to the model. Team-based care allows nurses and other health workers to take on routine monitoring and counselling, while physicians focus on complex cases. Field experience also highlights supply chains, since a protocol is of little use if the recommended drugs are out of stock. Programme evaluations have examined practical measures such as multi-month refills, decentralizing care closer to people's homes, and providing treatment free of charge to reduce out-of-pocket expenses.

Inequities and financial burden

The burden is unevenly distributed. Over three quarters of heart disease and stroke related deaths occur in low- and middle-income countries. Within countries, the picture is similar: people with lower incomes, those living in rural areas, and those with limited contact with health services are less likely to be diagnosed, to receive drug therapy, or to keep taking it. These gaps are closely linked to the social determinants of health.

Cardiovascular disease also imposes a financial burden on households and on health systems. Long-term drugs, repeated clinic visits, and hospital care for stroke or heart failure can push families into debt, especially where out-of-pocket payment dominates. Coverage through universal health coverage is widely seen as the mechanism that can protect households, but achieving it requires sustained financing and an adequately staffed primary care workforce.

Sex, age, and special populations

Sex differences in coronary disease

Women with coronary disease often differ from men in how they present and how they are managed. In a meta-analysis of confirmed acute coronary syndrome (ACS), women had higher odds of pain between the shoulder blades, nausea or vomiting, and shortness of breath, and lower odds of chest pain and sweating. The authors also found considerable overlap between the sexes and argued that the labels "typical" and "atypical" should be dropped. Women also tend to be about a decade older than men when they first present with coronary disease, and they are more likely to have several comorbidities at that point. Some of the delay in care is attributed to symptoms being attributed to other causes, and to women's lower perception of their own risk.

Diagnosis and treatment show a consistent pattern of disadvantage. Women are less likely to receive diagnostic imaging, percutaneous coronary intervention, and statin therapy, even when their clinical features are comparable to men's. Myocardial infarction with non-obstructive coronary arteries (MINOCA) and spontaneous coronary artery dissection (SCAD) are more common in women and are easily missed, which adds to underdiagnosis. Women with ST-elevation myocardial infarction have higher rates of bleeding and 30-day mortality, and sex hormones are thought to influence platelet function. Participation in cardiac rehabilitation is also lower among women. Clinical trials have historically under-enrolled women, which limits the sex-specific evidence available to guide care. Current efforts focus on sex-specific diagnostic pathways and on better representation of women in research.

Age and older adults

Cardiovascular risk rises steeply with age, mainly because atherosclerosis accumulates over decades. Older adults are more likely to have several conditions at once, including hypertension, diabetes, renal impairment, and heart failure, and they take multiple medications. These features complicate treatment decisions: benefits and harms of antithrombotic, lipid-lowering, and blood-pressure drugs must be weighed against frailty, falls, and bleeding risk, and the evidence for intensive targets is less certain in very old patients. Older adults have also been underrepresented in pivotal trials, so guideline recommendations for this group are often extrapolated from younger cohorts or from subgroup analyses. Efforts to broaden enrolment and to report age-specific results aim to close this gap.

Pregnancy-related cardiovascular risk

Pregnancy places a substantial load on the cardiovascular system. Cardiac output increases by 20–50%, while systemic vascular resistance falls by about 30%, and these changes begin early in gestation. Hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, are the best-recognised complications. In 2011 the American Heart Association formally recognised preeclampsia as a clinically important risk factor for later cardiovascular disease in women. Preeclampsia is associated with diastolic dysfunction and with later cardiomyopathy, and it may partly reflect shared genetic susceptibility, although the causal direction remains debated.

Peripartum cardiomyopathy is a rare form of heart failure that presents in the last month of pregnancy or within about five months after delivery, with reduced left ventricular ejection fraction in the classic form. It shows a strong association with preeclampsia and other hypertensive disorders; in one German series nearly half of affected women had a hypertensive disorder of pregnancy. A meta-analysis of observational studies reported that severe preeclampsia carried the highest odds of peripartum cardiomyopathy, and that advanced maternal age and multiple pregnancies were also associated with it. Black women in the United States have a markedly higher risk. Because its symptoms overlap with normal pregnancy, diagnosis is often delayed, and maternal mortality is substantially higher among affected women. Preserved-ejection-fraction heart failure is also recognised in the peripartum period, so the spectrum is broader than the classic definition suggests.

Cancer and cardiovascular disease

Cancer survivors have a higher risk of cardiovascular disease than the general population, and this has become an important clinical issue as survival from cancer has improved. Anthracycline chemotherapy can cause cardiomyopathy and heart failure, and radiotherapy to the chest causes dose-dependent myocardial and pericardial injury for which no safe threshold has been identified. Anthracycline and chest radiation are additive. Some targeted therapies, including HER2-directed antibodies such as trastuzumab, can also affect the heart; their cardiotoxicity is often reversible, but long-term cardiovascular risk appears higher in patients who also received anthracyclines. Tyrosine kinase inhibitors and vascular endothelial growth factor inhibitors can cause hypertension, arrhythmia, and ischaemia. Risk factors for long-term anthracycline-related cardiotoxicity include older age, chest irradiation, and pre-existing cardiovascular risk factors. Cardio-oncology has developed to address these problems through baseline cardiovascular assessment, surveillance during treatment, and the use of cardioprotective drugs in selected patients, while the evidence for routine prophylaxis remains mixed. Modern treatment protocols use fewer anthracyclines and less radiation than earlier regimens, which has been associated with a decline in cardiovascular complications.

History of research and clinical advances

Harvey and the closed circulation

William Harvey's 1628 treatise De motu cordis overturned the Galenic view that blood was a humour made and used up by the body. Through meticulous dissections and innovative experiments, Harvey demonstrated that blood flows in a continuous loop, propelled by the heart, which he identified as a pump. His argument was quantitative. The arithmetic suggested that the heart expelled far more blood than the body could have manufactured from food, so the same blood had to recirculate. His teacher Fabricius had studied the venous valves, work that was instrumental in the development of Harvey's theory. The book drew heavy criticism, and Harvey reportedly lost private patients as a result. Historians still treat it as the point where modern circulatory physiology began. Earlier writers such as Ibn al-Nafis apparently described pulmonary circulation in the Thirteenth Century, but Harvey's model of a closed loop was the one that became the foundation of physiology.

Electrocardiography and catheterisation

Willem Einthoven's string galvanometer, developed around 1901, recorded the heart's electrical activity as a sequence of waves that he labelled P, QRS and T. He received the 1924 Nobel Prize in Physiology or Medicine for this work, and the ECG remains a basic tool of diagnosis in cardiology.

Cardiac catheterisation began with a self-experiment. In 1929, the young Berlin surgeon Werner Forssmann passed a catheter from a vein in his arm into his own right atrium, watching its progress on a fluoroscope. His experiment was condemned at the time as foolhardy and dangerous, and he abandoned cardiology for urology. In 1941, Dickinson Richards and André Cournand at Bellevue Hospital in New York adapted the method. Their primary aim was to obtain mixed venous blood so that they could use the Fick principle to measure total pulmonary blood flow. The technique later allowed precise measurement of intracardiac pressure and blood flow, injection into the heart of drugs and of opaque material visible on X-ray photographs, which in turn made angiography and the diagnosis of structural heart disease possible. The 1956 Nobel Prize, shared by Cournand, Richards and Forssmann, recognised the discoveries concerning heart catheterisation and the circulatory changes they revealed.

The Framingham Heart Study

The Framingham Heart Study began in 1948 after the death of President Franklin Roosevelt, whose premature death in 1945 at the age of 63 helped prompt the programme. Congress funded it through the National Heart Act, and the original cohort of 5,209 residents ages 28-62 years was recruited between 1948 and 1952. Its first major findings, reported in 1957, noted a near four-times increase in the incidence of coronary heart disease for study participants with a blood pressure of 160/95 mm Hg or higher. In 1961, the investigators identified high blood pressure, high cholesterol and electrocardiographic left ventricular hypertrophy as major risk factors for coronary disease. These findings later formed the basis for multivariable 10-year and 30-year risk-prediction algorithms. The study also linked cigarette smoking to coronary disease in 1959, and its work popularised the term "risk factor" itself. By shifting attention from treating established disease to preventing it in people at risk, Framingham became a model for epidemiology of non-infectious diseases.

Statins, anticoagulants, stents and heart-failure drugs

Modern drug therapy was built largely through randomised trials. Statins trace back to the early 1970s, when Akira Endo isolated compactin from a fungus. Lovastatin, the first statin in clinical use, was approved in the United States in 1987. The Scandinavian Simvastatin Survival Study (1994) showed that lowering cholesterol in patients with coronary disease reduced mortality, establishing secondary prevention with statins as standard practice. The receptor work of Joseph Goldstein and Michael Brown, which underpins this field, was recognised by the 1985 Nobel Prize in Physiology or Medicine.

Heparin, discovered in 1916, was used clinically from the 1930s, and warfarin, derived from research on sweet clover disease, was approved for human use in the United States in 1954. Direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban and edoxaban were approved from 2010 onward and reduced the need for routine blood monitoring.

Andreas Grüntzig performed the first balloon angioplasty of a coronary artery in Zurich in 1977. Restenosis and abrupt vessel closure limited the technique until metal stents were introduced in the early 1990s, and drug-eluting stents, which slow neointimal growth, were approved in the United States in 2003 and 2004.

In heart failure, digoxin had been used since William Withering's 1785 account of foxglove, but the modern era began with ACE inhibitors such as captopril (1981). Trials then established beta-blockers, aldosterone antagonists, sacubitril–valsartan and SGLT2 inhibitors as disease-modifying therapies. Not every trial confirmed expectations: the Cardiac Arrhythmia Suppression Trial (1989) found that antiarrhythmic drugs given after myocardial infarction increased mortality, a lesson that reshaped the requirement for evidence-based medicine.

Open questions and current research

Residual risk and new therapeutic targets

Many patients who reach guideline targets for blood pressure and LDL cholesterol still have cardiovascular events, and this residual risk is a central problem for the field. Lipoprotein(a), or Lp(a), is one of the most studied candidates. Its level is largely set by genetics, and it is not reliably lowered by statins. The most consequential recent result is negative. On 4 September 2026, Novartis reported topline results from the phase 3 Lp(a)HORIZON trial: pelacarsen, an antisense drug, lowered Lp(a) in 8,323 people with elevated Lp(a) and established atherosclerotic disease, but it did not reduce major adverse cardiovascular events. The full data had not been published at the time of writing, so the reasons for the null outcome, such as the size of the effect on Lp(a) or the choice of endpoints, remain open.

Newer agents, including the small-interfering RNA drugs olpasiran and lepodisiran, produce deeper and longer-lasting Lp(a) reductions in early trials. Their outcome trials are still running, with OCEAN(a)-Outcomes expected to finish around the end of 2026 and ACCLAIM-Lp(a) around 2029. Genetic and observational studies suggest that Lp(a) contributes causally to disease, but the HORIZON result shows that lowering a biomarker does not by itself establish that events will fall. Inflammation is the other major target. The trial of canakinumab, which blocks interleukin-1β, reduced recurrent events independently of lipid lowering, but at the cost of more fatal infections. Colchicine has shown a smaller benefit in several trials, and newer IL-6 pathway inhibitors are under investigation. Whether reducing inflammation can be made safe and specific enough for routine use is unresolved.

Regenerative medicine, cell therapy and gene therapy

Repairing damaged myocardium is a long-standing goal, but the evidence is uneven. Cell therapy trials in acute myocardial infarction have been largely negative for more than a decade, whereas results in heart failure have been more encouraging. The phase III CHART-1 trial, which used a sham-controlled design with cardiopoietic mesenchymal cells, found that the overall quality-of-life difference at one year was not statistically significant. Benefit was confined to patients with advanced left ventricular enlargement, and in that subgroup it was associated with fewer deaths and hospitalisations. By contrast, the ALLSTAR trial of cardiosphere-derived cells was stopped early after an interim analysis showed no difference in scar size, which was judged futile. Meta-analyses report modest gains in ejection fraction without a clear mortality signal, but they call for larger randomised trials with longer follow-up. The mechanism is also debated: whether injected cells engraft and become muscle, or mainly act through paracrine signalling, remains uncertain.

Gene therapy is at an earlier stage for cardiovascular disease. Early-phase human trials have tested in vivo gene editing of PCSK9 to permanently lower LDL cholesterol, which could in principle replace repeated injections. For cardiac muscle itself, viral vector delivery faces problems of immune response, limited durability and uneven distribution across the heart. Current evidence for both approaches is confined to small or early-phase studies, so their clinical value cannot yet be judged.

Artificial intelligence in ECG, imaging and risk prediction

Deep learning applied to the standard electrocardiogram can detect findings that are not visible to the human eye, such as reduced ejection fraction or structural abnormalities. A preprint analysis of about 38,000 UK Biobank participants reported areas under the curve of 0.877 for left ventricular hypertrophy and 0.883 for left atrial enlargement. Another model, validated across five cohorts from the United States, Brazil and the United Kingdom, was reported to add predictive value beyond conventional risk factors. However, many models are still trained on single-centre or homogeneous datasets, and external validation remains uneven.

Subgroup performance is a serious concern. One ECG deep learning model for heart failure was reported to perform significantly worse in young Black patients, especially Black women, which illustrates how algorithmic bias can widen existing disparities. Prevalence also changes what a result means. In one illustrative calculation, a model with 98.8% sensitivity and 44.8% specificity had a positive predictive value of only 1.8% where the condition affected 1% of the population, but 8.6% at 5% prevalence. Validation therefore needs to report performance across sex, age, ethnicity and device types, and to test models in the populations and settings where they will actually be used. Similar questions apply to AI in echocardiography, cardiac MRI and risk prediction, and they connect to wider issues of data-privacy and informed-consent.

Reducing global inequities in prevention and care

The most unresolved question is how to deliver effective prevention and treatment where the burden is greatest and resources are scarcest. Low- and middle-income countries carry a large share of cardiovascular deaths, yet most of the proven therapies, such as statins, antihypertensives and antiplatelet drugs, are often unavailable, unaffordable or not delivered by trained staff. Strategies under study include primary-health-care models that use task-sharing and standardised protocols, low-cost combination pills, and reliable supply chains for generic medicines. Evidence on which packages are cost-effective, how they should be financed, and how well they hold up outside trial settings is still limited. The same questions apply to digital and AI-based tools: they may help where specialist capacity is scarce, but only if they are validated in local populations and do not replicate the gaps that already exist in health-system access.

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