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  • Inheritance and Cardiovascular Disease

    Edwin M. Knights Jr., M.D.

    Published Date : January 11, 2006

    As the leading cause of death in the United States is cardiovascular disease (CVD), with over 700,000 deaths attributable annually to the diseases of the heart and nearly 170,000 more resulting from cerebrovascular diseases in 2000, we should take a look at the role of inheritance. We know that lifestyle is important and that the risk factors include high blood pressure, diabetes, smoking, high blood cholesterol and advanced age. We can alter our lifestyles to reduce the risk, but molecular scientists have already found many genetic contributions to the disease. Family history which includes the interaction among enviromental, genetic and behavioral elements, provides a reliable means of assessing CVD.

    Persons who discover they’re in the high-risk category usually respond to this threat by adopting CVD risk-reducing behavior. (Ref. Table 1)


    Table 1.
    CVD Risk-Reducing Behaviors in Persons with CVD History Risk
    Ref.: McCusker ME et al: Family history of heart disease and cardiovascular disease risk-reducing behaviors.
    Eating fewer high-fat foods
    Eating more fruits and vegetables
    Increasing physical activity
    Trying to stop smoking
    Cholesterol checked in periodically
    Low-dose aspirin use



    Because CVD involves so many physiological functions and varieties of tissue (e.g., muscle fibers, elastic tissue, endothelial linings of arteries, fat, blood platelets, etc.), the investigations are taking place on many fronts.

    Strategies for Treatment

    The best strategy for dealing with genetic heart disease is to identify those who are at risk as early as possible and begin treatment which can minimize the effects of the inherited traits. It has been found that the correction of lipoprotein disorders is effective in slowing down the clinical progression of the disease in some patients, especially the reduction of low density cholesterol. But 80 percent of individuals who develop heart disease have normal cholesterol levels, so it’s apparent that the treatment has to be somewhat more specific. Although so far most of the educational efforts have stressed the reduction of low density cholesterol (LDL) in the blood, there are many other lipoprotein disorders involved and overcoming these metabolic traits could save very many lives as well as billions of dollars now spent on the prevention and treatment of early onset heart disease.

    Numerous studies are disclosing that many genes can play roles in this disease. Here are just some currently under investigation (not necessarily in the order of importance):
    ACE, ADH-3, ApoA1, ApoE, apo(a), beta-ENaC and gamma-ENaC, CETP, Gly46OTrp, HPA-2 Met, VNTR B, ITGB3, LDLR, PTGIS, UCP-3. Please excuse us if we’ve overlooked your favorite gene, but over 250 different ones have implicated in coronary artery disease. These genes have vastly different functions and some of them have multiple variants. There are also other genes associated with hypertension. High blood pressure afflicts about 25 percent of adults world-wide and is a major risk factor for fatal heart attacks.

    Lipoprotein Research

    An example of ongoing genetic research on heart disease are studies of a lipoprotein, Lp(a) that resembles the low density cholestrol (LDL) which doctors dread. It has an attached abnormal protein. Plasma levels are genetically determined by a chromosome 6 locus and it’s inherited in a mendelian dominant fashion, so about half of the children whose parents have high Lp(a) levels will develop a similar condition. Its presence has been shown to be a risk factor for heart attacks and for clotting combinations.

    Better Than Cholesterol Testing?

    High levels of apolipoprotein B (apoB) and low levels of apolipoprotein A-1 (apoA-1) have been found to be predictive of fatal myocardial infarction (MI), regardless of serum cholesterol levels. Dr. Goran Walldius and his associates in Sweden collected data on over 175,000 men and women and found that apoB concentrations and the apoB/APOA-1 ratio positively correlated with increased risk of fatal MI. These tests may eventually supplant cholesterol studies for assessment of MI risk, but the assay methods and quality assurance values need improvements before the tests can be used routinely.

    Genetic Aspects of High Blood Pressure

    Hypertension, or high blood pressure, affects around 25 percent of adults world-wide and is a major risk factor for fatal heart attacks, along with stroke, kidney failure and heart failure from congestive heart disease. It affects over 50 million Americans. A research group led by Richard Lifto identified two genes which cause a kidney disorder and lead to hypertension. These genes, WNK1 and WNK4, have mutations adversely affecting mechanisms regulating blood pressure, and the researchers hope that it will be possible to develop new specific medications which could provide another way to reduce fatal heart disease. Hypertension research is obviously complex because there are so many causes.

    Other scientists from the University of Cambridge and Incyte, studying the molecular basis of type 2 diabetes, used SNP technology which they reported as confirming a key gene responsible for this type of diabetes, severe insulin resistance and early onset hypertension. The research is an example of what Incyte refers to as the “candidate gene approach” to identify novel disease pathways and drug targets, using biology and bioinformatics combined with proprietary and public gene sequences to identify genes which would be potential targets for specific drugs. Detection of polymorphic genes plus genotyping technologies help establish the relationship between diseases and potential medications.

    Another investigative avenue is followed at Wake Forest University, where they are investigating the regulation of genes involved in vascular disease. They are also studying various mechanisms, such as enzymes, which the human body has developed to repair DNA damage at the cellular level.

    Research is also under way to see if any anti-hypertensive therapy can be tailored to specific genetic variations. A protein called “adducin” which is found on the inner surface of cell membranes, has a genetic variant known to increase the retention of sodium by the kidneys. Investigators feel that indentifying this variant would help recognize patients who could be treated effectively with diuretics, greatly decreasing their chances of experiencing a stroke or MI.

    Early Death from Cardiovascular Disease

    Is your heart too big? Did one or more of your relatives die at an early age from CVD or stroke? If so, there are some conditions besides hypertension which could have caused this early demise. One of them is cardiomyopathy. Being a big-hearted person is usually considered a compliment but its implications for a long, healthy existence can be quite dire, enough to make you heavy-hearted instead. What physicians call “hypertropic cardiomyopathy”

    (HCM) is actually the dilatation of one or both ventricles, the two large chambers which pump blood out of your heart, accompanied by impaired contraction of the walls during the pumping process. This often causes heart failure, with a high rate of sudden death, and can be a major reason to consider heart transplantation.

    Hypertrophy of the heart’s left ventricular wall, which pumps bood throughout most of your body, greatly affects morbidity and the mortality from such conditions as MI, congestive heart failure and stroke. It occurs in 16 percent of whites, 33 to 43 percent of African-Americans and from 22 to 60 percent of people with hypertension. In Britain the incidence is reported as 1/500. Heritability of HCM is 26 percent in whites and 70 percent in African-Americans. Several chromosomal loci are currently under study and may help us to understand the genetics.

    The genetic factors aren’t yet well understood, but some studies at the University of Ottawa involve a protein thought to take part in energy expenditure and may possibly be involved in the effects weight loss have on obese women when they take energy-restricted diets. At McGill, studies of ACE genotypes in sporadic HCM found no differences from the general population, but there may be genetic abnormalities not yet recognized. B. D. Lowes and associates at the University of Colorado have found other genetic influences in patients with HCM; these affect contractility and enlargement of cardiac muscle. This is just a glimpse of busy research projects spanning the globe.

    Sticky Platelets Found at Fault

    Two genetic abnormalities increasing the risk of early onset cardiac death have been found by Dr. J. Mikklesson in Finland. These variants, which were demonstrated in 20 percent of white males in his series of 700 autopsies, occured in 60 percent of people who were under the age of 55 when they died suddenly of cardiac causes. Deaths were attributed to increased platelet adhesion which had resulted in old organized blood clots in the coronary arteries. Organized blood clots, or thrombi, are gradually penetrated by multiple tiny blood vessels coming from the underlying muscular walls of the blood vessels. Instead of being dissolved, they become permanent obstructions which can even become calcified, narrowing or completely blocking the lumens of the vessels which nourish the muscular walls of the heart.

    Homecysteinemia

    A third condition to consider as a possible cause of your relative’s death at an early age is a rare, but deadly disease known as homocysteinemia.

    Children who have this disease develop lesions of the heart and brain at an early age. They can have a stroke as early as age 20 years and 18 percent die by the age of 30. Adults with elevated homocystein levels also have a high risk of stroke.

    The Role of Infection

    The importance of infectious agents in myocardial infarctions has been recognized for some time and is now under more intense investigation, including evaluation of the prophylactic use of certain antibiotics either to prevent MI or lessen the inflammatory reaction. So far there has been no conclusive evidence that antibiotics are useful in preventing MI but no doubt there are other studies yet to be reported. It also raises the possibility that one day it might be feasible to vaccinate persons at risk.

    All in a Heartbeat -- Just Too Fast

    Back in 1930, three doctors named Wolff, Parkinson and White described a peculiar phenomenon in which the hearts of apparently healthy young people suddenly would begin to pound rapidly, or as they put it, were prone to paroxysmal tachycardia. For some unknown reason, it was especially common in China, but the Wolff-Parkinson-White syndrome also affects up to 3/1,000 persons in Western countries and can cause sudden death. It was found to be heritable as an autosomal dominant disorder, so there is strong familial involvement. A gene responsible for this syndrome was described in 2001 by Gollob and numerous other investigators. (The ratio of affected family members to the investigators was only about 3:1, which gives some idea of the intensity of the study.) The cause of the condition was found to be a “missense mutation” on this gene.

    Blame It on Mom!

    As we learn more about mitocondrial DNA (mtDNA), we find that its proper function is essential for normal cellular metabolism. As you recll, it’s passed down unmodified from a mother to all her offspring and very much involved with energy production. Mutations of mtDNA are already catalogued and linked to degenerative diseases; they often involve entire systems rather than discrete organs and especially affect those organs which require a lot of energy. Some mitochondrial defects are acquired, rather than inherited.

    Defects from mtDNA may appear at birth or may not be apparent until middle age. The ones affecting heart muscle can block the cardiac conduction which controls heartbeat and cause sudden death. Government grants are now available to study the role of mtDNA in such conditions as ischemic heart disease (lack of proper nourishment and oxygen supply to the heart walls), idopathic dilated cardiomyopathy (the heavy-hearted patients) and various heart conditions associated with aging.

    A Drink a Day, If your Genes Say “O.K.”

    There are some epidemiological studies and innumerable self-serving interpretations of these studies reporting a reduced risk of MI associated with a moderate consumption of alcohol. The mechanisms for this symbiotic relationship are still under debate and could also include environmental factors, such as lifestyle, or variables in the alcoholic beverages, such as red vs. white wine.

    A polymorphism in the gene for alcohol dehydrogenase type 3 (ADH3) is known to alter your rate of alcohol metabolism. Lisa M. Hines and a jolly group of researchers studied the relationships among this ADH3 polymorphism, the level of alcohol consumption and the risk of MI in 396 patients in whom MI had been recently diagnosed. These were compared with almost twice that number of strictly sober controls. Records were also kept of the patients’ and the controls’ HDL levels. Subjects homozygous of an allele associated with a slow rate of ethyl alcohol oxidation, compared with those with the allele associated with a fast rate, showed a lower risk of MI. Moderate alcohol consumption was associated with a decreased risk of MI in 3 genotype groups if the participants consumed at least one drink per day. As compared with the control subjects, patients who’d experienced a MI had a higher prevalence of diabetes, angina and hypertension and were more likely to have a parent who’d had MI before age 60. The patients consumed less alcohol, took part less often in vigorous exercise, had higher cholesterol and lower HDL levels.

    The conclusions were that moderate drinkers (loosely defined as one drink per day) homozygous for the ADH3 allele have a substantially decreased risk of MI. Men who consumed this quantity and were homozygous for the slow-oxidizing allele, had the greatest reduction in risk. In case you are wondering, they did NOT extrapolate these results to suggest that two or more drinks per day further reduced the risks for MI, perhaps leaving this research for a later date. They did remark that heavy consumption of alcohol puts one at risk for alcoholism, stroke and liver disease.

    Genetic Testing for CVD?

    As in many other diseases, gentic testing isn’t usually performed in CVD. Clinicians are more interested in evaluating cardiac risk and the results of their treatment in acute cases. Numerous modifications to life style, as shown in Table 1, have proved helpful. If you know you have familial hypercholesterolemia, you can contact registries which offer other supportive services.

    Meanwhile, important genetic research continues on the leading causes of CVD in the developed world. Each new finding brings a little better understanding of the problem and possible new opportunities to diagnose, treat or monitor heart disease. As we learn more about the numerous genetic aberrations which accompany some heart disease, it will enable physicians to personalize treatment and tailor medications so the most effective ones are administered in the most efficient manner. We previously mentioned indications that ethnic groups are responding differently to the medications in current use. Knowing you are descended from ethnic group in which a particular beta-blocker isn’t effective could be a highly valuable by-product of your genomic/genealogy research, especially as alternative beta-blockers have now been developed.

    SELECTED REFERENCES

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    Lifton RP: Molecular genetics of human blood pressure variation. Science 1996; 272: 676-680

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    Schwartz K, Chassagne C, Boheler KR: The molecular biology of heart failure. J Am Coll Cardiol 1993; 22, Suppl A: 30A-33A

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    Ellesworth DL et al.: Coronary heart disease: at the interface of molecular genetics and preventive medicine. Am J Prev Med 1999; 15 (2): 122-133

    Inherited Cholesterol Diseases and Familial Hypercholesterolemia Register

    CDC: MMWR. Decline in Deaths from Heart Disease and Stroke -- United States, 1900-1999. Aug 6, 1999; 48: (30) 649656

    Anderson JL: Infection, antibiotics, and atherothrombosis -- End of the road or a new beginning? N Engl J Med 2005; 352: 1706-1709

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