Atherosclerosis, lipids and ischaemic heart disease

The liver holds a cholesterol pool fed by dietary cholesterol arriving in chylomicron remnants, by cholesterol returning from tissues in HDL and LDL, and by its own synthesis from acetyl-CoA; it drains the pool into VLDL, into bile as free cholesterol and, above all, into bile acids, which are the only quantitatively important route of disposal. Synthesis proceeds from acetyl-CoA through HMG-CoA to mevalonate, the committed step catalysed by HMG-CoA reductase in the endoplasmic reticulum, then through isoprene units and squalene to lanosterol and cholesterol. The reductase is the control point: cholesterol represses its transcription through the SREBP system and speeds its degradation, glucagon inactivates it by phosphorylation, insulin activates it, and statins inhibit it competitively. Cholesterol 7-alpha-hydroxylase begins bile acid synthesis, producing the primary acids cholic and chenodeoxycholic acid, which are conjugated with glycine or taurine, secreted, and in the gut deconjugated and dehydroxylated by bacteria to the secondary acids deoxycholic and lithocholic acid; about 95 percent is reabsorbed in the ileum and returned by the portal vein, so the pool of a few grams circulates several times a day, and bile acids returning to the liver inhibit their own synthesis. Because lipids are insoluble, plasma carries them in lipoproteins, a core of triglyceride and cholesterol ester inside a shell of phospholipid, free cholesterol and apoproteins that direct the particle. Chylomicrons, made in the enterocyte with apoB-48, carry dietary triglyceride; lipoprotein lipase on capillary endothelium, activated by apoC-II, releases the fatty acids and the remnant is cleared by the liver through apoE. VLDL, made in the liver with apoB-100, carries endogenous triglyceride; lipase strips it to IDL and then to LDL, which is two thirds cholesterol ester and is taken up by tissues through the LDL receptor, which recognises apoB-100; when receptors are saturated LDL enters the arterial wall. HDL, made in the liver and gut with apoA-I, collects cholesterol from cells through the ABCA1 transporter, esterifies it with LCAT and returns it to the liver directly or by transfer to VLDL and LDL (CETP), which is why HDL is protective. In familial hypercholesterolaemia the LDL receptor is absent or defective, LDL is not cleared, cholesterol rises to 8 to 12 mmol/L in heterozygotes and more in homozygotes, hepatic synthesis is not suppressed, and premature atherosclerosis, tendon xanthomas and corneal arcus follow.

Arteriosclerosis means hardening of arteries and has three patterns: arteriolosclerosis of small vessels, hyaline (homogeneous pink wall thickening in hypertension and diabetes) or hyperplastic (onion-skin layers in malignant hypertension); Mönckeberg medial calcification of muscular arteries in the elderly, harmless because the lumen is preserved; and atherosclerosis, the disease of elastic and large muscular arteries that causes most cardiovascular death. Its risk factors are age, male sex and family history (non-modifiable) and hyperlipidaemia, hypertension, smoking and diabetes (the major modifiable ones), with obesity, inactivity, stress, hyperhomocysteinaemia and inflammation adding risk. The response-to-injury hypothesis describes it as chronic inflammation of the intima. Endothelial injury or dysfunction from turbulent flow, hypertension, smoking, hyperlipidaemia or toxins increases permeability and adhesion; LDL enters the intima and is oxidised; monocytes adhere, enter and become macrophages that ingest the oxidised LDL through scavenger receptors and turn into foam cells, the fatty streak; platelets and macrophages release growth factors that recruit smooth muscle cells from the media, which proliferate and lay down collagen, forming the fibrous cap; the core beneath accumulates lipid, dead foam cells, cholesterol crystals and calcium. The plaque narrows the lumen slowly, but its dangerous events are acute: rupture or erosion of the cap exposes the core and triggers thrombosis, haemorrhage into the plaque expands it, fragments embolise, and the weakened media dilates into an aneurysm. An aneurysm is a localised abnormal dilatation of a vessel; true aneurysms involve all three layers and are saccular or fusiform, most often atherosclerotic in the abdominal aorta below the renal arteries, where they rupture when large; a false aneurysm is a contained leak; a mycotic aneurysm follows infection of the wall. Syphilitic aortitis, a tertiary syphilis lesion, is an obliterative endarteritis of the vasa vasorum that scars the media of the ascending aorta, producing a tree-bark intima, aneurysm and dilatation of the aortic ring with aortic regurgitation. Aortic dissection is a tear of the intima through which blood enters the media and splits it, usually in hypertensive men over fifty or in young patients with Marfan syndrome and cystic medial degeneration; it presents with tearing chest pain radiating to the back and kills by rupture into the pericardium, occlusion of branches or aortic regurgitation.

Ischaemic heart disease is myocardial ischaemia from coronary flow inadequate for demand, more than 90 percent of it from atherosclerosis, and it presents as four syndromes: angina pectoris, myocardial infarction, chronic ischaemic heart disease with heart failure, and sudden cardiac death. Stable angina is exertional chest pain relieved by rest or nitrates, from a fixed stenosis of 70 percent or more; Prinzmetal angina is pain at rest from coronary spasm; unstable angina is new, worsening or resting pain from a ruptured plaque with a non-occlusive thrombus and is the prelude to infarction. Infarction begins when a thrombus on a ruptured plaque occludes the artery: contractility fails within a minute, irreversible injury begins after 20 to 40 minutes at the subendocardium, and the wavefront of necrosis spreads outward to become transmural in three to six hours, so reperfusion within that window salvages muscle. Left anterior descending occlusion infarcts the anterior wall, apex and anterior septum (40 to 50 percent), right coronary occlusion the inferior and posterior wall and posterior septum (30 to 40), circumflex occlusion the lateral wall (15 to 20). The infarct is invisible for the first few hours, then shows coagulative necrosis with wavy fibres, neutrophils by 12 to 24 hours (peaking at three days when the infarct is yellow and softest), macrophages and granulation tissue from about a week, and a firm grey scar by six to eight weeks. Complications are arrhythmia (the commonest cause of death in the first hours), contractile failure and cardiogenic shock, fibrinous pericarditis, mural thrombus and embolism, rupture of the free wall (tamponade), septum or papillary muscle at three to seven days when the wall is softest, ventricular aneurysm, and the autoimmune Dressler pericarditis weeks later. Sudden cardiac death, usually a lethal arrhythmia from ischaemia or a scar, follows severe coronary disease in most adults and cardiomyopathy or channelopathy in the young. Chronic ischaemic heart disease is progressive failure from scarred, hibernating myocardium. Hypertensive heart disease is concentric left ventricular hypertrophy (wall over 2 cm, heart over 500 g) without dilatation in response to pressure load, leading to diastolic failure, atrial fibrillation and, eventually, dilatation; cor pulmonale is the right ventricular counterpart from pulmonary hypertension. The markers confirm necrosis: myoglobin rises within one to four hours but is not cardiac-specific; creatine kinase MB rises at four to eight hours, peaks at 24 and returns to normal in 48 to 72 hours, making it useful for re-infarction; cardiac troponin I and T rise at three to six hours, peak at 24 and stay raised for seven to ten days, and are the most specific and sensitive test; lactate dehydrogenase (LDH1 above LDH2) rises late and lasts a week, now historical; aspartate aminotransferase rises but is non-specific.

Therapy starts with diet, weight, exercise and stopping smoking, and drug choice follows the abnormality: LDL cholesterol is the target in atherosclerotic disease and familial hypercholesterolaemia, triglycerides in hypertriglyceridaemia and pancreatitis risk. Statins (atorvastatin, rosuvastatin, simvastatin) competitively inhibit HMG-CoA reductase; the liver, deprived of cholesterol, increases LDL receptors and clears LDL from plasma, lowering LDL by 25 to 60 percent, lowering triglycerides modestly and raising HDL slightly, and they reduce cardiovascular events and mortality in secondary and high-risk primary prevention through lipid lowering and plaque stabilisation. Adverse effects are myalgia, rarely myositis and rhabdomyolysis (more with high doses, fibrates and CYP3A4 inhibitors such as clarithromycin and grapefruit), raised transaminases, and a small rise in diabetes; they are contraindicated in pregnancy. Ezetimibe blocks the NPC1L1 transporter that absorbs cholesterol in the small intestine, lowers LDL by about 18 percent and adds to a statin. Bile acid sequestrants (cholestyramine, colestipol, colesevelam) bind bile acids in the gut, interrupt the enterohepatic circulation and force the liver to make new bile acids from cholesterol, raising LDL receptors; they are not absorbed, so they are safe in pregnancy and children, but cause bloating and constipation, raise triglycerides and impair absorption of fat-soluble vitamins and drugs such as warfarin and digoxin. Fibrates (gemfibrozil, fenofibrate) activate PPAR-alpha, increase lipoprotein lipase and fatty acid oxidation, lower triglycerides by up to 50 percent and raise HDL, but cause gallstones, myopathy (especially gemfibrozil with a statin) and raise LDL in some patients. Niacin (nicotinic acid) inhibits VLDL secretion and lipolysis, lowers LDL and triglycerides and raises HDL more than any other drug, but flushing (prostaglandin-mediated, reduced by aspirin), hyperglycaemia, hyperuricaemia and hepatotoxicity limit its use. PCSK9 inhibitors (evolocumab, alirocumab), injected antibodies, stop PCSK9 from degrading LDL receptors, lower LDL by 60 percent on top of a statin and are used in familial hypercholesterolaemia and statin intolerance. Omega-3 ethyl esters lower triglycerides.

Angina is treated by lowering the four determinants of oxygen demand (heart rate, contractility, preload as wall stress, afterload) or by raising supply. Nitrates (sublingual glyceryl trinitrate for attacks, isosorbide mononitrate and transdermal patches for prophylaxis) release nitric oxide in smooth muscle, raise cyclic GMP and relax veins above all, so preload, ventricular size and wall tension fall; they also dilate large coronary arteries and relieve spasm. Glyceryl trinitrate acts within minutes and lasts less than half an hour because of hepatic first-pass metabolism, which is why it is given under the tongue; continuous exposure causes tolerance, so a nitrate-free interval of eight to ten hours is kept each day. Adverse effects are headache, flushing, postural hypotension and reflex tachycardia, and nitrates are contraindicated with sildenafil and related phosphodiesterase-5 inhibitors, which can cause profound hypotension. Calcium channel blockers reduce calcium entry into vascular and cardiac muscle: dihydropyridines (amlodipine, long-acting nifedipine) dilate arterioles and coronary arteries and lower afterload, and are the drugs for vasospastic angina; verapamil and diltiazem also slow the rate and reduce contractility, cutting demand, and are alternatives when beta-blockers cannot be used, with the same caution about heart block and heart failure. Beta-blockers lower heart rate, contractility and pressure, lengthen diastole for coronary perfusion, and reduce infarction and death after an infarct; they are first-line for stable angina but worsen vasospastic angina and are avoided in asthma and decompensated failure. Clinically, stable angina is a predictable retrosternal pressure radiating to the arm, neck or jaw on exertion, lasting minutes and relieved by rest or glyceryl trinitrate; it is investigated with a resting ECG (often normal), an exercise ECG or stress imaging, and coronary angiography when revascularisation is considered, and managed with risk-factor control, aspirin, a statin, a beta-blocker or calcium channel blocker, nitrates, and angioplasty with stenting or bypass grafting for left main or three-vessel disease. The acute coronary syndromes present with pain at rest lasting more than 20 minutes, sweating, nausea and dyspnoea, and are separated by the ECG and troponin: ST elevation means an occluded artery and demands immediate reperfusion by primary angioplasty or, if unavailable, thrombolysis; non-ST-elevation infarction and unstable angina are treated with antiplatelet drugs, anticoagulation, beta-blockers, statins and early angiography. Complications are watched for in the first days: arrhythmia, failure, shock, rupture, pericarditis and embolism.