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Mutant Gene Predicts Heart Disease
DD genotype may stimulate 
increased ACE activity
The 
increased blood pressure 
eventually leads to ventricular 
hypertrophy. 



โรคหัวใจ/
    Heart Disease


หัวใจวาย - หัวใจล้ม / 
Congestive Heart failure



 




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 หัวใจวาย - หัวใจล้ม / Congestive Heart failure      

Mutant Gene Predicts Heart Disease
Sean Henahan 
--------------------------------------------------------------------------------------------------------------

Heart failure is the only major cardiovascular disease that continues to increase in incidence, with 400,000 new cases diagnosed in the U.S. each year. Heart failure is now the most common cause of death among patients 65 years of age and older. Moreover, the prognosis for heart failure patients remains poor, with a 50% mortality rate within five years of diagnosis. Japanese researchers have recently identified a mutant gene that is associated with an increased risk for high blood pressure and enlargement of the left ventricle, both risk factors for heart failure. 

High blood pressure is a major factor contributing to heart failure. In patients with heart failure, the heart cannot adequately continue pumping all the blood that circulates through it, resulting in a back-up of blood into the veins and fluid accumulation in the body. In response to an elevated blood pressure, the heart works harder and harder, eventually leading to compensatory enlargement of the left ventricle. 

This enlargement or hypertrophy of the left ventricle is strongly associated with cardiovascular morbidity and mortality. In addition to high blood pressure, obesity, insulin sensitivity, and family history are all factors which have been linked to the development of left ventricular hypertrophy. 

The gene the Japanese researchers identified encodes for angiotensin converting enzyme (ACE), which also appears to be an independent risk factor for left ventricular hypertrophy. Researchers at Shiga University studied 268 individuals chosen at random from an outpatient clinic, using ultrasound to measure the size of the patients' left ventricles. They also performed polymerase chain reaction evaluations of genomic DNA (from peripheral leukocytes) to determine the patient's ACE genotype. The study revealed that variations of the gene with two key deletions called the "DD genotype" were significant predictors of left ventricular hypertrophy.. 

The researchers believe that the DD genotype may stimulate increased ACE activity in heart and blood vessels. This would lead to formation of angiotensin II, a powerful hormone that constricts blood vessels and raises blood pressure. The increased blood pressure eventually leads to ventricular hypertrophy. 

The current findings contribute to other experimental and clinical studies suggesting a role for the cardiac-renin-angiotensin system in the development of left ventricular hypertrophy. In particular, the data suggest intracardiac formation of angiotensin II independent of the circulating renin-angiotensin system. 

ACE has long been recognized to play a role in the development of high blood pressure. Indeed, a whole class of drugs, the ACE-inhibitors, has become one of the most effective treatments for high blood pressure. However, large clinical studies have shown that treatment with ACE-inhibitors can also reduce left ventricular enlargement in those with a propensity for developing it. However, different drugs in the same class produce varying degrees of benefit. The current findings may help explain these differences. 

The Japanese study complements other recent studies indicating an increased risk of heart attack and stroke in patients with the DD genotype. The findings should help in the study of the causes of heart failure in general and could lead to diagnostic tests to identify high risk patients. 

For more information see: Iwai et al., Circulation, 12/94. 

INTRODUCTION

Over the past decade, much interest has developed regarding the role of the renin-angiotensin system in cardiovascular disease. Specifically, the angiotensin-I converting enzyme (ACE), the enzyme responsible for converting angiotensin I to angiotensin II, has been the focus of a considerable number of investigations due to its apparent widespread effects on multiple organ systems, including the heart, the vascular system, and the kidneys. Angiotensin has been shown to have vasoconstrictor activity on vascular endothelium and may thus play a role in the pathophysiology of hypertension. Also, angiotensin has been shown to stimulate smooth muscle hypertrophy and hyperplasia through the release of growth factors, such as platelet derived growth factor, and through the activation of proto-oncogenes (1). Recent advances in molecular biology have localized the ACE gene to chromosome 17 (2). Further analysis demonstrated a polymorphic region consisting of the presence or absence (insertion/deletion) of a 287 bp fragment (3).

Many studies have attempted to determine whether specific ACE genotypes are associated with certain traits or diseases. For instance, Rigat et al. found that the insertion/deletion polymorphism accounted for nearly half the variance of serum ACE levels, with deletion homozygotes (DD genotype) having significantly higher serum ACE levels (4). Subsequently, Cambien et al. demonstrated that the DD genotype is more frequent in patients who had a myocardial infarction (MI) and thus constitutes a risk factor for MI, particularly in those patients considered to be at low risk (i.e. without hypertension, high plasma lipid levels, or smoking history) (5). Further analysis revealed that, in patients with previous MI, there was increased frequency of the DD genotype among those with a parental history of MI. This suggested that genetic variation at the ACE locus may be involved in the risk for MI (6).

In another study, Raynolds et al. found an increased frequency of the DD genotype in patients with ischemic or dilated cardiomyopathy, indicating that the ACE DD genotype may be a risk factor for heart failure associated with these types of cardiomyopathy (7). An increased frequency of the DD genotype has also been associated with left ventricular hypertrophy (LVH) (8), coronary artery disease (9), familial hypertrophic cardiomyopathy (HCM), and a family history of sudden cardiac death (SCD) (10). In addition, the DD genotype has been found to influence the phenotypic expression of left ventricular hypertrophy in HCM (11).

 

 

ACE ABSTRACTS: Angiotensin-I converting enzyme genotype DD is a risk factor for coronary artery disease.

Beohar N, Damaraju S, Prather A, Yu QT, Raizner A, Kleiman NS, Roberts R, Marian AJ Department of Medicine, [Baylor College of Medicine, Houston, Texas 77030, USA.]

BACKGROUND: Coronary artery disease (CAD) is a polygenic disease whose phenotypic manifestation is due to interaction of a number of environmental factors with an underlying genetic background. A number of genes, including the angiotensin-I converting enzyme (ACE) gene, have been implicated in the pathogenesis of CAD. ACE can affect oxidation of LDL, endothelial cell function, and smooth muscle cell migration and proliferation: all important components of atherosclerosis. A variant of ACE gene, genotype DD is associated with a higher plasma level of ACE and an increased risk of myocardial infarction, and cardiomyopathies. In this study, we sought to determine the distribution of ACE genotypes and the frequency of allele D in patients with CAD undergoing coronary angioplasty.

METHODS: DNA from 182 white patients undergoing coronary angioplasty and 338 apparently healthy white individuals was amplified by polymerase chain reaction (PCR) in the region of the polymorphism using the previously published protocol.

RESULTS: PCR amplification of alleles I and D resulted in 490 bp and 190 bp products, respectively. ACE genotype DD was present in 47% of patients with CAD as compared to 30% in the general population (p = 0.0002, Odds ratio 2.7). The frequency of allele D was 0.68 in patients with CAD and 0.55 in general population, respectively (p < 0.0001). Genotype DD was associated with CAD only in males (54% vs. 30%, p = 0.0001, Odds ratio 2.0), but not in female patients. There was no association between the frequency of ACE genotype DD and the prior history of myocardial infarction, or the extent of CAD. The frequency of ACE genotype DD was the highest among patients with restenosis following angioplasty (55%), however, the difference was not significantly changed as compared to those without restenosis (40%).

CONCLUSIONS: ACE genotype DD is more common in patients with CAD as compared to the general population, indicating that genotype DD is a genetic risk factor for CAD.

 

 

The DD polymorphism of the angiotensin converting enzyme (ACE) gene[1] is associated with higher serum levels of ACE, and an increased frequency of this allele has been found in patients with hypertrophic cardiomyopathy[2] and left ventricular hypertrophy.[3] However, an initial association with ischemic heart disease[4] has not been confirmed in subsequent larger studies,[5,6] and a putative association between the DD allele and the development of either ischemic or idiopathic dilated cardiomyopathy[7] has not been substantiated.[8,9] Recently, Andersson and Sylvan[10] found an association between poorer survival, an increase in left ventricular mass, and the DD genotype in white patients with idiopathic heart failure. They suggested a possible pathophysiologic pathway linking the ACE gene polymorphism with myocardial hypertrophy and survival. We have found that the DD allele is less frequent in Chinese populations[11] and that there is no association between the presence of the DD allele and end-stage heart failure from ischemic or idiopathic dilated cardiomyopathy.[9] We have now extended our studies to assess the relation of the ACE gene polymorphism and prognosis in Chinese patients with heart failure. In addition, we have also assessed the potential role of polymorphisms of the angiotensinogen and the angiotensin type I receptor (ATIR) gene. The angiotensinogen M235T TT genotype has been associated with increased serum angiotensinogen levels in whites and is reputed to be associated with hypertension and coronary artery disease.[12] Similarly the ATIR A1166C polymorphism has been associated with hypertension in white subjects,[13] particularly in those with increased aortic stiffness,[14] and has been reputed to act in synergy with the ACE DD genotype as a risk factor for myocardial infarction.[15] We have recently shown that in a healthy Chinese population, the frequencies for the angiotensinogen genotypes and the ATIR genotype are significantly different from white populations.[16] The angiotensinogen M235T variant is generally much higher in Asian populations (70% to 73% in Chinese) compared with white populations (10% to 24%) but lower than that in blacks from Africa (84% to 88%).[16,17] Also, Chinese have a lower frequency of the ATIR CC genotype (0%) compared with whites (6% to 10%). Therefore we were interested to determine whether polymorphisms of the angiotensinogen and ATIR genes are possibly more relevant in a Chinese population than ACE polymorphism. Thus we have compared the influence on survival and clinical course of polymorphisms not only of the ACE gene, but also angiotensinogen and ATIR genes in a cohort of Chinese patients with clinical heart failure.

 

 

Cell biology and genetics of angiotensin in cardiovascular disease.

Dzau VJ.

Falk Cardiovascular Research Center, Stanford University School of Medicine.

GROWTH-PROMOTING EFFECTS OF ANGIOTENSIN: Angiotensin, a vasoconstrictive peptide, is now known to be an agent of vascular and cardiac growth and may directly influence the pathophysiology of coronary artery disease and ventricular remodeling. Vascular growth occurs when angiotensin activates autocrine and paracrine growth factors, including fibroblast growth factor, transforming growth factor beta-1 and platelet-derived growth factor, and is modulated by endothelium-derived vasodilators and growth inhibitors. ANGIOTENSIN AND CARDIOVASCULAR DISEASE: The presence of angiotensin converting enzyme (ACE) and angiotensin II has been demonstrated in vascular tissue, and these local substances are causally involved in the development of vascular lesions. Similarly, angiotensin can stimulate cardiac myocyte growth and matrix modulation. Cardiac tissue ACE is implicated in ventricular remodeling in the course of progressive heart failure. A genetic variant of the ACE gene has been reported to be associated with increased risks of cardiovascular pathology. ACE INHIBITOR THERAPY: To date, studies of ACE inhibitor treatment in human patients have not demonstrated any prevention of restenosis after angioplasty. However, recent clinical trials in postmyocardial infarction reported that ACE inhibitor therapy reduces recurrent myocardial infarction and prevents cardiac enlargement. Long-term prospective trials are currently being conducted to examine the effects of ACE inhibitor therapy on coronary ischemic events and coronary atherosclerosis, as evaluated by angiography or intravascular ultrasound, and the relationship between coronary events and ACE gene polymorphism.


PMID: 7965271 [PubMed - indexed for MEDLINE] 



Angiotensin Converting Enzyme


The major regulator of mineralocorticoid synthesis is the renin/angiotensin system. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion by the adrenal gland.

High circulating plasma ACE is associated with high circulating levels of PAI-1 (plasminogen activator inhibitor-1), the major inhibitor of fibrinolysis in the circulation.

There is an insertion/deletion (I/D) of a 287 bp fragment within intron 16 in the ACE gene the allele frequency of which is I=44% and D=56%. Assuming simple Mendelian inheritance, the genotype frequencies (in Caucasians) would be: D/D= 36%, D/I=40% and I/I=24%. 

The plasma ACE concentration (in IU/L)in patients with the D allele is higher than that in patients with the I allele, e.g., D/D= 18 IU, D/I= 14.5 IU, and I/I 11.0 IU.

The D/D genotype is associated with left ventricular hypertrophy (LVH), with or without hypertension, odds ratio = 2.63 at 95% confidence

The D allele is associated with myocardial infarction, increased plaque instability, stent restenosis, LVH, ischemic or idiopathic cardiomyopathy, coronary artery disease, and other cardiovascular diseases, including diabetes mellitus and diabetic nephropathy.

ACE may modulate, either directly or indirectly, the above cardiovascular diseases. Thus ACE inhibitors may have advantages over other antihypertensive drugs.

References: 

1. Schunkert, H., et al., (1994) Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. New Eng. J. Med. 330:1634-1638. 

2. Abbud, Z. A. et al., (1998) Angiotension-Converting Enzyme Gene Polymorphism in Systemic Hypertension. Am. J. Cardio. 81-244-246 

3. Kario, K. et al. (1997) Hypertension nephropathy and the gene for angiotensin-converting enzyme. Arterio., Thromb. Vas. Biol. 17:252-256 

4. Nakano, Y. et al. (1997) Angiotensin I-converting enzyme gene polymorphism and acute response to Captopril in essential hypertension. Am. J. Hyperten. 10:1064-1068. 

5. O’Malley, J. P. et al. (1998) Angiotensin-converting enzyme DD genotype and cardiovascular disease in Heterozygous Familial Hypercholesterolemia. Circulation 97:1780-1783 

6. Ribichini, F. et al. (1998) Plasma activity and insertion/deletion polymorphism of angiotensin I-converting enzyme. A major risk factor and a marker of risk for coronary stent restenosis. Circ. 97:147-154. 

7. Ohmichi, N. (1997) Relationship between the response to the angiotensin converting enzyme inhibitor Imidapril and the angiotensin converting enzyme genotype. Am. J. Hyperten. 10:951-955 

8. Mondorf, U. F. et al. (1998) Contribution of angiotensin I converting enzyme gene polymorphism and angiotensinogen gene polymorphism to blood pressure regulation in essential hypertension. Am. J. Hyperten. 11:174-183. 

9. van Essen, G. G., et al. (1996) Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy. The Lancet 347:94-95. 

10. Kim, Duk-Kyung, et al. (1997) Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1. Arterio., Thromb. Vas. Biol. 17:3242-3247. 

11. Jacobsen, P. et al. (1998) Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy. Kidney International 53:1002-1006.



Angiotensin-converting enzyme test

Definition
This test measures blood levels of angiotensin-converting enzyme (ACE), also known as Serum Angiotensin-Converting Enzyme (SASE). The primary function of ACE is to help regulate arterial pressure by converting angiotensin I to angiotensin II.

Purpose
The ACE test is used primarily to detect and monitor the clinical course of sarcoidosis (a disease that affects many organs, especially the lungs), to differentiate between sarcoidosis and similar diseases, and to delineate between active and inactive sarcoid disease. Elevated ACE levels are also found in a number of other conditions, including Gaucher's disease (a rare familial disorder of fat metabolism) and leprosy.

Precautions
It should be noted that people under 20 years of age normally have very high ACE levels. Decreased levels may be seen in the condition of excess fat in the blood (hyperlipidemia). Drugs that may cause decreased ACE levels include ACE inhibitor antihypertensives and steroids.

Description
ACE plays an important role in the renin/aldosterone mechanism which controls blood pressure by converting angiotensin I to angiotensin II, two proteins involved in regulating blood pressure. Angiotensin I by itself is inactive, but when converted by ACE to the active form, angiotensin II, it causes narrowing of the small blood vessels in tissues, resulting in an increase in blood pressure. Angiotensin II also stimulates the hormone aldosterone, which causes an increase in blood pressure. Certain kidney disorders increase the production of angiotensin II, another cause of hypertension. Despite the action of ACE on blood pressure regulation, determination of this enzyme is not very helpful in the evaluation of hypertension (high blood pressure).

Preparation
Determination of ACE levels requires a blood sample. The patient need not be fasting.

Risks
Risks for this test are minimal, but may include slight bleeding from the puncture site, fainting or feeling lightheaded after venipuncture, or hematoma (blood accumulating under the puncture site).

Normal results
Normal ranges for this test are laboratory-specific but can range from 8-57 U/ml for patients over 20 years of age.

Abnormal results
Serum ACE levels are elevated in approximately 80-90% of patients with active sarcoidosis. Thyroid hormone may have an effect on ACE activity, as hypothyroid (low thyroid) patients, as well as patients with anorexia nervosa with associated findings of hypothyroidism, may have low serum ACE activity. ACE can also be decreased in lung cancer (bronchogenic carcinoma).



Books

Cahill, Mathew. Handbook of Diagnostic Tests. Springhouse, PA: Springhouse Corporation, 1995.

Jacobs, David S., et al. Laboratory Test Handbook. 4th ed. New York: Lexi-Comp Inc., 1996.

Pagana, Kathleen Deska. Mosby's Manual of Diagnostic and Laboratory Tests. St. Louis: Mosby, Inc., 1998.

Source: Gale Encyclopedia of Medicine




Angiotensin Converting Enzyme

The major regulator of mineralocorticoid synthesis is the renin/angiotensin system. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion by the adrenal gland.

High circulating plasma ACE is associated with high circulating levels of PAI-1 (plasminogen activator inhibitor-1), the major inhibitor of fibrinolysis in the circulation.

There is an insertion/deletion (I/D) of a 287 bp fragment within intron 16 in the ACE gene the allele frequency of which is I=44% and D=56%. Assuming simple Mendelian inheritance, the genotype frequencies (in Caucasians) would be: D/D= 36%, D/I=40% and I/I=24%. 

The plasma ACE concentration (in IU/L)in patients with the D allele is higher than that in patients with the I allele, e.g., D/D= 18 IU, D/I= 14.5 IU, and I/I 11.0 IU.

The D/D genotype is associated with left ventricular hypertrophy (LVH), with or without hypertension, odds ratio = 2.63 at 95% confidence

The D allele is associated with myocardial infarction, increased plaque instability, stent restenosis, LVH, ischemic or idiopathic cardiomyopathy, coronary artery disease, and other cardiovascular diseases, including diabetes mellitus and diabetic nephropathy.

ACE may modulate, either directly or indirectly, the above cardiovascular diseases. Thus ACE inhibitors may have advantages over other antihypertensive drugs.

References: 

1. Schunkert, H., et al., (1994) Association between a deletion polymorphism of the angiotensin-converting-enzyme gene and left ventricular hypertrophy. New Eng. J. Med. 330:1634-1638. 

2. Abbud, Z. A. et al., (1998) Angiotension-Converting Enzyme Gene Polymorphism in Systemic Hypertension. Am. J. Cardio. 81-244-246 

3. Kario, K. et al. (1997) Hypertension nephropathy and the gene for angiotensin-converting enzyme. Arterio., Thromb. Vas. Biol. 17:252-256 

4. Nakano, Y. et al. (1997) Angiotensin I-converting enzyme gene polymorphism and acute response to Captopril in essential hypertension. Am. J. Hyperten. 10:1064-1068. 

5. O’Malley, J. P. et al. (1998) Angiotensin-converting enzyme DD genotype and cardiovascular disease in Heterozygous Familial Hypercholesterolemia. Circulation 97:1780-1783 

6. Ribichini, F. et al. (1998) Plasma activity and insertion/deletion polymorphism of angiotensin I-converting enzyme. A major risk factor and a marker of risk for coronary stent restenosis. Circ. 97:147-154. 

7. Ohmichi, N. (1997) Relationship between the response to the angiotensin converting enzyme inhibitor Imidapril and the angiotensin converting enzyme genotype. Am. J. Hyperten. 10:951-955 

8. Mondorf, U. F. et al. (1998) Contribution of angiotensin I converting enzyme gene polymorphism and angiotensinogen gene polymorphism to blood pressure regulation in essential hypertension. Am. J. Hyperten. 11:174-183. 

9. van Essen, G. G., et al. (1996) Association between angiotensin-converting-enzyme gene polymorphism and failure of renoprotective therapy. The Lancet 347:94-95. 

10. Kim, Duk-Kyung, et al. (1997) Polymorphism of angiotensin converting enzyme gene is associated with circulating levels of plasminogen activator inhibitor-1. Arterio., Thromb. Vas. Biol. 17:3242-3247. 

11. Jacobsen, P. et al. (1998) Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy. Kidney International 53:1002-1006.




 






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