Genetic aspect in CCV DISEASES

Dr. Triwani, M.Kes Medical Biology Faculty of Medicine Sriwijaya University

Genetics in Cardiovascular Disease

Over 5% of all cataloged genes have some affect on the heart Hundreds of genes are expected to be essential for normal development and physiology of the cardiovascular system Up to 50% of patients with extreme mutations die by the age of 40
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Genetics in Cardiovascular Disease

Most forms of heart disease appear to have three components with varying amounts of importance depending on the disease
Environmental Risk Factors Genetic (or Inherited) Risk Factors Chance

In General most genetic variation has small effects - the larger the effects the rarer the disease
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Genetics in Cardiovascular Disease

Patients with rarer forms of heart disease often have a clear genetic link that predisposes them. But the multifactorial nature and unclear role of the environment on the outcome disease cloud the connections between specific genes and most forms of cardiovascular disease

Genetic Risk Factors and Diseases

Known Risk Factors - that themselves have recognized genetic components:
Diabetes Hypertension Cholesterol (Hypercholesterolemia) Hyperlipidemia

Genetic Risk Factors and Diseases

Genes that increase ones risk of Heart Disease:
Homocysteine (Homocystinuria) Fibrinogen Apolipoprotein E Apolipoprotein B

More than 300 genes have so far been associated with cardiac hypertrophy. Genetic factors are believed to be responsible for approximately two-thirds of the cases of high blood pressure (hypertension). "Responsibility genes" have been identified as the specific cause of dilated cardiomyopathy and another six "susceptibility genes" have been noted.
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Cardiovascular Diseases with Multiple Mutations

Most cardiovascular diseases are a result of multiple abnormalities in many different genes on several chromosomes (polygenic) with no clear phenotypic differences. Hypertension is an example Up to 20 genes are presumed to be related to hypertension.

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Cardiovascular Diseases with Multiple Mutations

Renin-Angiotensin System Kallikrein System Nitrous Oxide System Membrane (Ion) Channels Catecholamines Cardiovascular Peptide Neuropeptides

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Cardiovascular Diseases with Multiple Mutations

Epidemiological, biochemical, and genetic studies have suggested that the pathogenesis of a majority of cardiovascular diseases are too complex to expect to find a cause-and-effect relationship between gene and disease. But through the study of some of the rare more direct cardiac diseases the mechanisms underlying hypertension, atherosclerosis, hypertrophic cardiomyopathy, and other diseases
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Cardiovascular disorder
Congenital heart disease Common genetic determinants of coagulation and fibrinoysis Cardiomyopathies Familial dysrythmias Molecular basis of hypertension Preeclampsia Genetic determinants of atherosclerotic heart disease and other occlusive arterial disorders Hereditary disorders of the lymphathic and venous system
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Congenital heart disease (CHD)

Heart malformation are the most common form of birth defect, affecting about 7 in 1000 newborn. All of birth defects, chromosomal aneuploidy should be suspected in any newborn with CHD A specific pattern dysmorphic feature may suggest a syndrome Maternal history known teratogens Clinical examination karyotype analysis Combination family history and dysmorphic feature identify defect associated with monogenic syndrome
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Chromosomal defects and heart formation

Aneuploidy the term means not good set. Monosomy (Turner syndrome) trisomy ( Downs-21, Edwards-18, Pataus-13) and tetrasomies (cat eyes-22p, Pallister-Killians-12p) Chromosome deletion syndrome detected more recently by using FISH or molecular analysis
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Chromosomal defects and heart formation

Phenotype/genotype correlation: the CATCH Phenotype CATCH22: cardiac defect, abnormal facies, T-cell deficit, cleft palate, hypocalcemia due to 22q11 deletion DiGeorge syndrome.

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Genes resonsible for Congenital Heart malformation as monogenic traits

ELN supravalvar aortic stenosis JAG1 peripheral pulmonary artery stenosis

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Environmental cause and teratogen syndrome

Maternal diabetes Maternal drug ingestion Maternal phenylketonuria

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Common genetic determinants of coagulation and fibrinolysis

Thrombotic disorders are major cause of morbidity and mortality . Classified : affecting the venous system Characterized by fibrin rich thrombi Affecting the arterial system Characterized by platelet rich thrombi Both venous and arterial thrombotic disorders, abnormalitas
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Activation of the coagulation cascade and platelet adhesion following endothelial damage

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Risk factor for thrombosis

Venous thrombosis Contribution of genetic factor family history,
many individual presenting with premature thrombosis. Commonly deficiencies in the anticoagulant proteins, protein C, protein S and anticoagulant pathway

Arterial thrombosis
Complex interactions between environmental and genetic factors. Change in plasma levels of component of the hemostatic system are related to the pathogenesis of cardiovascular disorders
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Risk factor for thrombosis

Arterial thrombosis (cont)
Several coagulation and fibrinolytic factors, including: f ibrinogen, factor VII, von Willebrand factor, PAI-1 and tPA with atherothrombotic event. Activation of coagulation progression etherosclerosis and manifestation of acute thrombosis Contribution of Genetic factor has been indicated by the clustering of Cardiovascular diseases within families CAD
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Cardiomyopathies
Definition : disease of the myocardium associated with cardiac dysfunction 4 different classes: hypertrophic cardiomypathy (HCM), dilated cardiomypathy (DCM), restrictive cardiomypathy (RCM) and arrythmogenic right ventricular cardiomypathy (ARVC). 2 additional categories: unclassified cardiomypathy and specific cardiomypathy
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Hypertrophic Cardiomyopathies
Clinical presentation, diagnosis, pathology and prognosis ( not to be explained) Genetics : - usually familial - autosomal dominant - sporadic disease uncommon - sarcomeric contractile gene mutations - eight genes confirmed - -myosin heavy chain most frequently affected
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From monogenic disease such as familial hypertrophic cardiomyopathy comes the concept of physiological convergence in which disparate genetic mutations independently cause a common pathophysiological abnormality that leads to disease. In theory it should be possible to triangulate (shaded) the point of physiological convergence from at least 2 independent genes.

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Dilated Cardiomyopathies
Genetics o Mendelian inheritance in 25% of patien o Usually autosomal dominant, rarely Xlinked o 8 autosomal DCM loci with unknown genes o 5 genes known: laminA/C, -myosin HC, actin, tafazzin (X-linked), dystropin (X-linked)
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Familial dysrythmias and conduction disorders

Dysrythmias typically are thought to occur due to primary or secondary abnormalities in cardiac electrophysiology Familial inheritance of dysrythmias and conduction disorders indicates that genetic factors play an integral role in development this abnormalities.

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Familial dysrythmias and conduction disorders

Specific cardiac dysrythmias Atrial and ventricular tachydysrythmias Sinus node dysfunction (SND) Atrioventricular block (AV block) Primary abnormalities in cardiac rhythm: ventricular tachydysrythmias Long QT syndrome (LQTS)

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Familial dysrythmias and conduction disorders

Long QT syndrome (LQTS) LQT is an inherited cardiac disorder that increases the risk of sudden death from ventricular arrhythmias. So far mutations in four separate genes have been identified and connected to this disease through different mechanisms that result in the same outcome.

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Familial dysrythmias and conduction disorders

Long QT syndrome (LQTS) Normally the sodium channel initiates a myocellular action potential and closes, remaining closed for the rest of the action potential.
- Mutation : Causes repetitive and openings of the channel - Results : Prolonged action potentials

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Familial dysrythmias and conduction disorders

Long QT syndrome (LQTS) Normally activation of the potassium channel terminates cardiac action potential. - Mutation: Reduces the functioning of the channel - Results : Prolonged action potentials

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Familial dysrythmias and conduction disorders

Long QT syndrome (LQTS) Normally subunits assemble and form a functioning ion channels - Mutation : Causes the formation of aberrant
subunits that do not co-assemble with normal subunits into functioning channels - Results : 50% reduction in functioning channels Delayed myocellular re-polarization

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Molecular BASIS of hypertension

Genetic basis of essential hypertension is complex. Individual blood pressure levels result from both genetic predisposition (30%) and environmental factor (50%). Several loci, depend on age and sex Interaction with other genes

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Molecular BASIS of hypertension

Monogeneic form of hypertension Candidate genes in human essential hypertension Other candidate genes

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Preeclampsia
Preeclampsia is a common and sometimes dangerous multisystem disorder of pregnancy, especially notable for hypertension and proteinuria. Main symptom and sign: hypertension, proteinuria, edema, coagulation and platelet disturbances, liver involvement and neurological abnormalities including cortical blindness and convulsion.
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Preeclampsia
Eclampsia and preeclampsia more common in primiravida, higher recurrent risk. Genetic model: dominant inheritance of the disease allele and equal penetrans of the heterozygous and homozygous genotype Phenotype transient hypertensi Gene expression: plasminogen activator inhihitor type 1 (PAI-1) mRNA and protein is enhanced in syncytiotrophoblast
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Genetic determinants of atherosclerotic heart disease and other occlusive arterial disorders

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 Multifactorial nature of common conditions such as ischemic heart disease involves several risk factors each of which have heterogeneous molecular origins at both the gene and the mutation levels. Interaction between different genes and with the environment (not shown) adds further complexity.
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Risk factor for atherosclerotic vascular disease

Male sex Advanced age Hypertension Diabetes mellitus/ Insulin resistance Hypercholesterolemia elevated low-density lipoprotein (LDL) Low high-density lipoprotein HDL) Family history of a relative with symptomatic arterial occlusive diseases occuring < 55 years of age Cigarette smoking Obesity Inactivity Elevated serum uric acid

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Emerging risk factor of atherosclerotic arterial disease

Hyperhomocysteinemia Dyslipidemia - Elevated Lp(a)

- Atherogenic lipoprotein phenotype

Factor predisposing to thrombosis

- Elevated fibrinogen - Elevated factor VII - Elevated factor V - Elevated PAI-1

Markers of inflamation
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Hereditary disorders of the lymphathic and venous system

A large number of Mendelian and multifactorial disorders affect either primarily or secondarily, the development, function and natural history (aging) of veins and lymphatics.

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Disorder of venous system Inherited venous malformation

Autosomal dominant forms consisting primarily of congenital, progresive venous malformation. One form: cutaneous and mucosal surface

Cerebral cavernous malformation

rare vascular lesion that may involve any part of central nervous system.

Varicose veins
increase caliber and tortuosity associated with engorgement of the superficial veins of the leg, with the saphenous being most prominent. Varicous maybe congenital but develop in middle-age in the vast majority of affected people 43

Disorders of the lymphatic system

Diffuse, acquired blockage of lymphatics, such as by fibrosis, tumor and infection, usually result in edema of the body parts distal to the blockage. If thoracic duct is blocked, anastomosing channels develop between the lymphatic system and systemic veins, and edema does not persist. Hygroma aneuploidy: Turner syndrome, Noonan syndrome
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Gene Therapy in Cardiovascular Disease

Genetic manipulation of cardiovascular tissue Gene therapy of restenosis Gene therapy of angiogenesis Gene therapy of vascular grafts Gene therapy for the heart

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Coronary heart disease

Environmental factors play a very important role in the aetiology of coronary heart disease, and many risk factors have been identified, including high dietary fat intake, impaired glucose tolerance, raised blood pressure, obesity, smoking, lack of exercise and stress

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Coronary heart disease

A positive family history is also important. The risk to first degree relatives is increased to six times above that of the general population, indicating a considerable underlying genetic predisposition

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Risk factors in coronary heart disease

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reference
Emery and Rimoin, 2002. Priciples and Practice of MEDICAL GENETICS, 4th ed. Churcill Livingstone. Vol. 1, Page 1239-1557 Down load internet journal

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