Heart disease and genetics

ALSO KNOWN AS: HD; atherosclerotic heart disease; cardiovascular disease; coronary artery atherosclerosis; coronary artery disease; CAD; coronary heart disease; CHD; ischemic heart disease

DEFINITION Heart disease is any abnormal condition of the myocardium (heart muscle) or coronary arteries. Perhaps because it is so common, coronary heart disease (CHD) is often used interchangeably with the term heart disease. CHD, however, refers more specifically to conditions that restrict blood flow through the coronary arteries. By far, the most frequent of these conditions is atherosclerosis, a buildup of fatty plaques inside the arterial walls. Although lifestyle plays a major part in the development of atherosclerosis and its progression to CHD, genetic factors are important determinants as well.

Risk Factors

Many interrelated risk factors contribute to CHD, with lipoprotein levels, oxidation, inflammation, and thrombosis playing central roles. Lipoproteins transport triglycerides and cholesterol through the blood; their concentrations are determined by diet, exercise, and heredity. The hereditary condition most strongly associated with CHD is familial hypercholesterolemia. Other factors affecting CHD risk (each with its own genetic component) include abdominal fat, diabetes, emotional stress, high blood pressure, hormone treatment after menopause, chronic kidney disease, metabolic syndrome, old age, alcohol abuse, and tobacco smoke. For genetic and environmental reasons, African Americans tend to be at higher risk for CHD than Caucasians, whereas Asians and Hispanics tend to be at lower risk. Males are at higher risk than females, but after menopause the risk evens out.

Etiology and Genetics

CHD is typically caused by a buildup of fatty plaques in one or more large coronary arteries, a process that often begins in childhood. Although the initiating events are not well understood, it is thought that plaque development occurs at sites of “damage” to the endothelium layer of cells lining the interior of the artery. These sites accumulate low-density lipoprotein particles (LDL cholesterol or LDL-C, often referred to as “bad” cholesterol). The oxidation of these particles incites an inflammatory response. As part of this response, macrophages engulf the oxidized LDL-C but end up being a major part of the problem when they consume too many particles and become foam cells. These cells and others, along with necrotic debris, turn into a fatty streak that triggers plan B: Seal off the area. This strategy is accomplished by creating a fibrous cap over the fat deposit and slowly calcifying the plaque from the bottom up, keeping it separate from the layer of smooth muscle cells that contract and expand the artery. This arrangement works well as long as the cap does not fracture, which it unfortunately does occasionally because of blood pressure and more attempts by the inflammatory system to clean things up.

A cracked plaque leaks debris into the artery that immediately triggers thrombosis (clotting). A clot that is not fully occlusive gets degraded but leaves a larger fibrous cap. Consequently, repeated rupturing and capping eventually leads to significant stenosis (narrowing of the artery) and ischemia (oxygen starvation). Stenosis makes it especially difficult for the heart to keep up with the demands of exercise, often leading to angina pectoris (chest pain). The acutely dangerous plaques, however, are generally smaller and fattier (less calcification) with unstable caps. Their greater tendency to rupture increases the probability of a thrombus that completely blocks the artery. When such blockage occurs in a large artery, it often leads to acute ischemia and heart attack.

CHD is a process with the above scenario playing out over a period of decades. It is perhaps not surprising, therefore, that genetic studies have now implicated hundreds of genes that affect CHD risk. The vast majority of genetic variants have small, modulating effects; but as shown years ago by the Nobel Prize-winning research of Michael Brown and Joseph Goldstein, there are some rare mutations that act as primary drivers of CHD. These mutations are typically associated with hypercholesterolemia and found most often in the gene encoding for the LDL-C receptor, responsible for LDL-C uptake by the liver and removal from the circulation. Other mutations causing hypercholesterolemia occur in the PCSK9 gene encoding proprotein convertase subtilisin/kexin type 9, an important determinant of LDL-C receptor number; in the APOB gene encoding apolipoprotein B-100, the major protein component of LDL-C and important determinant of binding to the LDL-C receptor (the resulting syndrome is also called familial defective apolipoprotein B-100 or FDB); and in the LDLRAP1 gene encoding the low-density lipoprotein receptor adaptor protein 1, important for translocating LDL-C and bound LDL-C to the interior of the cell for processing (the resulting syndrome is also called autosomal recessive hypercholesterolemia or ARH). A recessive mutation able to cause hypercholesterolemia independent of the LDL-C receptor has been identified in the CYP7A1 gene encoding cytochrome P450, family 7, subfamily A, 1 (also called cholesterol 7-hydroxylase); this is essential for converting cholesterol to bile acids and thereby preventing a build-up of LDL-C. These mutations are a testimony to the fundamental role played by LDL-C in the pathogenesis of CHD.

Several other single-gene disorders produce another type of dyslipidemia also considered causal for early-onset CHD. These mutations occur in pathways affecting the high-density lipoprotein carrier of cholesterol (HDL-C). HDL-C, often referred to as “good” cholesterol, has a number of beneficial characteristics that oppose plaque development, including and anti-inflammatory properties and its ability to compete with LDL-C in the transport of cholesterol. HDL-C also facilitates the processing of very-low-density lipoproteins (VLDLs) to LDL; high levels of VLDL are also a risk factor for CHD. Mutations affecting HDL-C levels leading to CHD are found in the ABCA1 gene encoding ATP-binding cassette transporter 1, critical for handing off cholesterol from cells to HDL (the resulting syndrome is also called Tangier disease). Mutations with variable (probability of being causal) for CHD are also found in the LCAT gene encoding lecithin-cholesterol acyltransferase, essential for the esterification of cholesterol for transport by HDL (the resulting syndrome is also called fish-eye disease or familial LCAT deficiency).

Other types of genetic variants strongly affect CHD risk at later ages. One of the best known is the APOE e4allele; the APOE gene encodes for apolipoprotein E, a major protein component of VLDL. Other variants affect HDL-C metabolism; they include APOA1 (apolipoprotein A-I), the primary protein component of HDL-C; and CETP (cholesterol ester transfer protein), another enzyme responsible for esterifying cholesterol.

Additional genetic variants affect oxidation, the immune response, and thrombosis in the pathogenesis of CHD. Risk alleles affecting the oxidation of LDL-C occur in PON1 (paraoxonase 1), PON2, and LOX1 (lectin-like oxidized LDL receptor). Variants affecting the immune response are found in CD14, TNFSF4 (tumor necrosis factor superfamily 4), ALOX5 (arachidonate 5-lipoxygenase activating protein), and LTA4H (leukotriene A4 hydrolase). Variants affecting thrombosis are present in genes such as F5 and F7 (coagulation factors V and VII, respectively), necessary components of the blood coagulation cascade; FGB (fibrinogen beta chain), a glycoprotein cleaved by thrombin to form fibrin; ICAM1 (intracellular adhesion molecule 1), a cell surface glycoprotein expressed on endothelial and immune cells; and THBD (thrombomodulin), an endothelial membrane receptor that binds thrombin.

Genome-wide association studies have indicated risk alleles for CHD in many more genes. In most cases, however, the molecular identity of the genes has not yet been determined. An unidentified variant having one of the larger effect sizes is located on the short arm of chromosome 9 (9p21), near the CDKN2A and 2B genes. These two genes along with the noncoding gene ANRIL are primary candidates for being the genes involved. It is thought that the genetic variant may increase CHD risk by affecting vascular remodeling.

The development of new artificial intelligence, or AI, technology, has shown promise in helping researchers understand the correlations between genetics and heart disease. For instance, in 2024, researchers at Icahn School of Medicine at Mount Sinai used AI technology to train computers to search through the health records of hundreds of thousands of patients. In this way, they identified seventeen genes in which coding variations play a role in CHD. Discoveries such as this help increase understanding of the factors leading to heart disease and how it can be prevented and treated.

Symptoms

The development of atherosclerosis in coronary arteries has no symptoms. It is only in the later stages, when blood flow to the heart becomes impaired, that problems manifest themselves clinically. The signs are most noticeable during exercise or exertion: unusual fatigue, lightheadedness, palpitations, and a feeling of pressure on the chest. Other forms of physical stress such as anger, eating a heavy meal, or cold exposure can also trigger symptoms. Examination by a physician should be scheduled as soon as possible; damage done by CHD can soon lead to arrhythmia and heart failure (inability to pump sufficient blood). Symptoms of an impending heart attack are similar to those above but persist more than five minutes, even in the absence of exertion. They include nausea, heartburn, breathlessness, cold sweats, and nonspecific pain, pressure, or discomfort in the chest (which may radiate to the shoulders, upper back, neck, jaw, or arms). For women, it has been suggested that these signs are frequently more subtle, oftentimes with no chest pain (only discomfort). If a heart attack is suspected, then the victim should call for an ambulance immediately and chew an aspirin. Pain at an exact spot or chest pain related to breathing is typically not symptomatic of heart attack.

Screening and Diagnosis

CHD is the leading cause of death in developed countries for both men and women; the number of deaths attributable to CHD in the United States averages about 697,000 per year. Screening for CHD risk should begin early in adulthood. This is accomplished by assessing blood pressure, family history, lifestyle, and biomarkers in the blood. The commonly used blood measurements are the fasting levels of glucose, total cholesterol, LDL-C (greater than 130 mg/dL = high risk), HDL-C (less than 40 mg/dL = high risk), triglycerides, homocysteine, and C-reactive protein (CRP), a marker of inflammation. Genetic tests are also becoming available for assessing CHD risk but their added value has not been established; the 9p21 variant noted appears to have a small amount of predictive value independent of standard blood tests.

A variety of tests are used to diagnose advanced atherosclerosis and CHD. The gold standard is angiography: a catheter is threaded through an artery that releases a dye for X-ray viewing of the blood flow to the heart. Other methods of visualizing heart and vascular function include computed tomography (CT), positron emission tomography (PET), magnetic resonance imaging (MRI), radionuclide imaging, and ultrasound imaging (Doppler and echocardiogram). A different kind of test, the electrocardiogram, measures abnormalities in the electrical impulses regulating the heart; this test and others are often conducted in combination with an exercise stress test. There exists a simple blood test that estimates the degree of coronary artery obstruction on the basis of changes in RNA levels measured across a large number of genes (CardioDX). Other blood tests quantify levels of the protein troponin to diagnose heart attack; thyroid hormone and the hormone BNP (B-type natriuretic peptide) are often measured to assess potential for heart failure.

Treatment and Therapy

Intervention usually begins with lifestyle changes—stopping smoking, managing stress, exercising more, eating less. Dietary recommendations also include taking in a greater proportion of calories from a variety of fruits, vegetables, beans (garbanzo, lima), whole grains (brown rice, oats, whole wheat), lean meats (chicken), oily fish (salmon, sardine, trout, tuna), tree nuts (almonds, pecans, walnuts), nonhydrogenated oils (olive, canola, sunflower), and low-fat dairy. These guidelines are meant to increase the intake of complex carbohydrates, soluble fiber, polyphenolic flavonoids, plant sterols, and omega-3 fatty acids while decreasing the intake of simple sugars, cholesterol, saturated fats, and trans fats. With the exception of omega-3 fatty acids and niacin, taking dietary supplements (vitamins B₆, B₁₂, C, and E and folic acid) has not proved to be effective. Niacin supplementation at high doses is beneficial for boosting HDL-C, although blood testing should be done for potential liver damage. Limited alcohol intake and moderately intense aerobic exercise (not necessarily at the same time) also improve HDL-C and provide other vascular benefits (limited alcohol means one drink per day for women, up to two for men). Reducing sodium intake relative to potassium intake helps lower blood pressure.

When diet and lifestyle changes are not sufficient, various drug options are available. High levels of bad cholesterol are usually treated using statins, which inhibit the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, needed for cholesterol synthesis. Statins also have antioxidant, anti-inflammatory, and plaque stabilizing benefits. Bile acid sequestrants and cholesterol absorption inhibitors are occasionally used to lower LDL-C as well. Low HDL-C is sometimes treated using fibrates. High blood pressure is typically treated using diuretics, beta blockers, or angiotensin converting enzyme (ACE) inhibitors. Thrombosis risk is treated using low-dose aspirin or drugs such as warfarin, clopidogrel, and prasugrel. Patients should not stop taking medications without consulting their physician; abrupt withdrawal can trigger a heart condition.

A number of therapies are used to treat coronary stenosis. The least invasive are medications such as nitroglycerin, ranolazine, and calcium channel inhibitors; these dilate the arteries to reduce chest pain. A common surgical procedure is to physically open the artery using a catheter, often done in conjunction with implanting a stent to hold the artery open. In cases where multiple arteries exhibit blockage, bypass surgery is often necessary to replace diseased arteries with large veins (usually from the legs). Treating arrhythmia is another specialty in itself; treatment options include various drugs, surgery, implants, and electric shock. Imminent heart failure requires a heart transplant or artificial heart.

It is also worth noting that the efficacy of most drug treatments for CHD is subject to significant genetic variation. Understanding this variation is an important aspect of selecting an optimal treatment regimen for each individual; genome-wide association studies will continue to be important in identifying new predictors of CHD risk. The results have strongly implicated many of the genes encoding p450 oxidase proteins (such as CYPC19 and CYP2C9), responsible for metabolizing xenobiotics (foreign compounds such as drugs and toxins). Other genes, such as KIF6 (kinesin family member 6), have variants that alter the efficacy of statins; and VKORC1 (vitamin K epoxide reductase complex, subunit 1) variants can markedly alter the effectiveness of warfarin.

Prevention and Outcomes

Preventing CHD requires all the lifestyle changes noted above. Any reduction in LDL-C or increase in HDL-C is also helpful regardless of baseline levels. Risk factors such as blood pressure, LDL-C, HDL-C, triglycerides, blood glucose, homocysteine, sodium, potassium, and C-reactive protein should be monitored with blood tests and regular checkups. Simple hygiene measures such as habitual brushing and flossing of teeth can also reduce inflammation (gingivitis) and CHD risk. Such lifestyle changes are critically important because once atheromatous plaques reach the fibrous stage, they are essentially permanent. A heart-healthy lifestyle is also important for good health regardless of genetic risk for CHD. Genetic testing is largely beneficial only for those with a family history of early-onset CHD so that treatment is initiated early and aggressively. For others, testing for one or a few risk alleles is fraught with uncertainty given the huge number of genetic and environmental interactions affecting penetrance.

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