Personalized Medicine for Cardiovascular Diseases PDF

Personalized Medicine for Cardiovascular diseases What are cardiovascular diseases (CVD)? Causes Major types Current available treatment Approach to Personalized Cardiology Cardiovascular disease (CVD) CVD is one of the most common causes of death worldwide. Personalized medicine based on human gene...

Personalized Medicine for Cardiovascular diseases What are cardiovascular diseases (CVD)? Causes Major types Current available treatment Approach to Personalized Cardiology Cardiovascular disease (CVD) CVD is one of the most common causes of death worldwide. Personalized medicine based on human genetics may be useful because CVD has heritable traits. A comprehensive approach including rare and common genetic variations provide useful information on the risk for CVD and the best approach is to reduce the risk. ~50% of the variance in heritability can be explained by genetics in CVD. The other 50% may be explained by acquired, environmental factors, such as lifestyle. Risk factors Age Absence of key nutritional elements, such as polyphenol antioxidants Diabetes mellitus Hypercholesterolemia (elevated cholesterol levels) and abnormal lipoprotein particle profile (cholesterol subtypes) Tobacco smoking High blood pressure Exposure to high levels of environmental noise Obesity Genetic factors/Family history of cardiovascular disease Physical inactivity/ Sedentary lifestyle Depression Cardiovascular disease (CVD) CVD includes the disease of the heart and blood vessels. Major diseases include heart disease, stroke and peripheral vascular disease. Disorders of the heart: Heart failure is when the heart no longer pumps properly Myocardial infarction/Heart attack, tissue death Disorders of the blood vessels: Hypertension, high blood pressure Atherosclerosis, plaque Stroke, blocked vessel Aneurysm, ballooning vessel Coronary Heart Disease Most common type of CVD = 20% of all deaths. Blood supply to the heart is decreased by narrowing arteries. Angina = blockage decreases blood flow to the heart and causes pain as a result of cramping of the heart muscle. Blockage = heart attack. Cerebrovascular Disease Disease of the arteries of the brain. Stroke = an interruption of blood supply to the brain. Caused by atherosclerosis. Stroke = blood vessel may also burst. Peripheral Vascular Disease Affects the blood vessels in the limbs. Arteriosclerosis = hardening of the arteries that interferes with blood supply to the muscles and skin. Close links with smoking and diabetes. Can result in gangrene and limb amputation Hypertension High Blood pressure results when blood moves through vessels at a rate higher than normal often due to arterial Plaque 140/90 mm Hg is considered hypertension. A silent killer because there are few symptoms. Can lead to a heart attack, stroke etc. Atherosclerosis Plaque is a deposit of fat and cholesterol beneath the inner ( epithelium) tissue of an artery Plaque that is stationary is called a thrombus and an embolus when it detaches and can move to distant sites. Associated with a stroke , heart attack and aneurysm Atherosclerosis and Hypertension Stroke Cerebrovascular accident (CVA) Usually, a cranial artery is blocked or bursts Part of the brain dies dues to lack of oxygen Symptoms may occur including numbness of hands or face, difficulty speaking and inability to see in one eye Atherosclerosis and Hypertension Heart attack Myocardial infarction (MI) Part of the heart tissue (muscle) dies due to lack of oxygen Can begin with angina pectoris, a pain that radiates down the left arm due to a blockage of a coronary artery Atherosclerosis and Hypertension Aneurysm A ballooning of a blood vessel Atherosclerosis and hypertension can weaken a vessel and cause ballooning The most affected is the abdominal artery or the arteries leading to the brain Blood clots can block vessels and cause CVD Dissolving blood clots: Drug treatment; t-PA (tissue plasminogen activator) is a drug that dissolves clots. Treating clogged arteries (surgery): Bypass surgery: usually, a vein from the leg is taken and used to bypass a clogged artery Stents: wire mesh cylinder inserted into a clogged artery to hold it open Angioplasty: a tube with a balloon is inserted into the clogged area and the balloon is then inflated to open the vessel A stent and angioplasty may be used in combination Clinical Applicability of Genetic Testing in CVD and Precision Medicine The diagnostic power of genetic testing is significant across the spectrum of CVDs, ranging from cardiomyopathies to life-threatening arrhythmias. Clarify disease diagnosis: Genetic testing can help to clarify the diagnosis of diseases that cause similar clinical presentation (e.g., cardiac hypertrophy could be TTR amyloidosis, Fabry disease, or sarcomeric HCM (hypertrophic cardiomyopathy) Facilitate cascade screening: Genetic testing can help to identify relatives at risk for CVD before disease symptoms manifest if a diseaseassociated variant is found in a proband and then screened for in relatives Direct more precise therapy: Genetic testing can help physicians choose appropriate treatments and plan appropriate timing of those treatments. For example, inherited connective tissue disease due to variants in ACTA2, MYH11 or TGFBR2 might prompt consideration of surgical intervention at a smaller aortic aneurysm diameter; Identify patients for targeted therapies, including antibody-based therapeutics, gene editing, and silencing technologies, are available or under development. Biomarker-guided therapy Biomarker-guided therapy is the use of biomarkers to tailor medical treatment, could assist in: (i) selection of therapy, (ii) evaluation of efficacy, (iii) optimal dose selection, and (iv) recognition and avoidance of side-effect Personalized Medicine approaches : (a) Conventional strategies assign treatments to large groups of individuals but take the risk that treatment may not be effective and/or not safe. (b) In precision medicine, individuals undergo comprehensive individualized characterization to decide about the right treatment for the right person. Depending on test performance, this precise treatment will be effective and free of adverse effects. Personalized Medicine approaches: Stratified approaches group individuals based on criteria such as sex, age, genetic background, ethnicity, biomarker studies, or imaging studies into groups that will then be managed uniformly. The panel A shows a general population that undergoes testing for risk stratification. Of the at-risk population, 40% develop disease despite preventative treatment. This may be due to the poor efficacy of the treatment or because the test wrongly classified subjects into the at-risk group despite being at no risk. Treatment of disease will then be based on further tests is only appropriate for female patients. Treatment A (b) Personalized approaches (Panel B) collect as much information as possible including genetic/genomic , imaging, and functional studies, individual lifestyle factors, and medical records and use integrative analysis methods to develop precise and individualized management strategies that will include all areas from disease prevention to therapeutic strategies. In this case, each patients is considered as individual unit. Personalized Medicine - dyslipidemias, including FH and its related diseases CVD has heritable traits - family history information is associated with CVD events. Genetic background (germline genetic variations) may be particularly useful for risk stratification because it can be assessed from birth without being affected by temporary environmental factors. Familial hypercholesterolemia (FH) provides a good example of the strong associations of CVD with human genetics. FH is an autosomal dominant disorder and is one of the most common Mendelian dyslipidemias associated with premature coronary artery disease. Typically, a rare mutation in the LDL receptor (LDLR) or its associated genes can lead to dysfunction of LDL metabolism, which can result in premature coronary artery disease. The genetic mutation status of FH is a biomarker for CVD risk. Early diagnosis and treatment with statins can substantially reduce the risk of CVD in FH patients. A portion of patients with clinical diagnosis of FH also develop Sitosterolaemia Sitosterolaemia is an autosomal recessive disease, show accumulation of plant sterols in blood and tissues. They have double mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) gene or the ATPbinding cassette subfamily G member 8 (ABCG8) gene, their clinical manifestations are similar to those in FH. In cases with Sitosterolaemia , ezetimibe is strongly recommended rather than statins. Mutation carriers of the ABCG5 or ABCG8 genes exhibit a better response to ezetimibe. PCSK9 inhibitors are less effective for patients with homozygous FH, especially those with double defective LDLR gene mutations Personalized Medicine for hyper LDL Cholesterolemia When the LDL cholesterol level is high (e.g., ≥180 mg/dl), clinical and genetic diagnosis of familial hypercholesterolemia (FH) should be considered because it can lead to differential treatment strategies Xanthomas are localized deposits under the skin surface, usually caused by high levels of blood lipids, or fats. Impact of genetic counseling in patients with familial hypercholesterolemia (FH) Information about genetically-estimated future cardiovascular risk based on the result of genetic testing. The primary endpoint is the plasma LDL cholesterol levels at 24 weeks. Secondary endpoints assessed at 24 weeks and 48 weeks include blood test results, smoking status, changes in the regime of lipid-lowering agents along with the Patient Satisfaction Questionnaire Short Form scores PM- arrhythmias Risk stratification of cardiac events in patients with LQTS according to genotype, age, and sex. LQTS (long-QT syndrome) is a widely established model for personalized medicine, because there are strong data showing a correlation of common genotypes of LQTS with disease phenotypes. LQTS is characterized by a prolonged QT interval on surface electrocardiogram and a propensity for life-threatening ventricular tachyarrhythmias, which results in fainting or passing out and sudden death LQTS can be subclassified into congenital and acquired forms. The congenital form (cLQTS) occurs in at least 1 in 2000 live births. The P-wave represents atrial activity, the QRS represents ventricular activation, and the QT interval represents ventricular recovery or repolarisation. In a patient with Long-QT syndrome, the QT interval is significantly prolonged, with repolarization delayed, leading to an increased risk of ventricular tachyarrhythmias (caused by irregular electrical signals in the lower chambers of the heart or ventricles). Genetic testing can identify a mutation in 75–80% of clinically-affected patients with congenital LQTS, as well as in some patients with acquired LQTS. Seventeen genetic forms of LQTS have been described, and the most prevalent forms are LQT1, LQT2, and LQT3. Empirically, ~50% of genotyped patients with LQTS show no cardiac symptoms throughout their life. Genotype–phenotype correlations in three LQTS subtypes showed that genotype, QTc interval, age, and sex were determinants of arrhythmic event risk Patients with LQT2 and LQT3 have a greater risk of events than LQT1 patients, and that individuals with a QTc duration >500 ms are at higher risk than subjects with a shorter QTc duration Personalized Medicine based on common genetic variations Both rare genetic variations and common genetic variations have been associated with CVD. Rare genetic variations in which a single variation typically exhibits a large effect. Common genetic variations tend to have smaller effects. Polygenic risk scores for particular phenotypes are assessed to determine whether accumulation of these small effect sizes is useful. Polygenic risk scores developed from approximately 6 million single nucleotide variations were robustly associated with CVD. Some individuals exhibited a high polygenic risk equivalent to that in monogenic FH (tenfold higher prevalence among patients with early-onset myocardial infarction). This high genetic risk can be reduced with statin therapy or a heathy lifestyle. Further studies are needed to clarify more specific pathways and therapeutic targets suitable for individuals with a high polygenic risk with specific combinations of single nucleotide variations (SNV). Monogenic versus polygenic contribution to early-onset myocardial infarction. Among patients suffering from early onset of myocardial infarction, ~1.7% were monogenic familial hypercholesterolemia (FH), whereas 17.3% were considered as polygenic high risk. Cardiomyopathies Hypertrophic cardiomyopathy (HCM), defined as diseases of the myocardium associated with cardiac dysfunction is slowly progressive, and manifests with near-normal life expectancy without symptoms to sudden cardiac death (SCD) in youth. The estimated prevalence of HCM in the general population is approximately one in 500. Approximately 60% of patients with HCM have a family history showing autosomal dominant inheritance. Mutations in genes encoding myocardial components, such as the sarcomere, account for 40–60% of HCM cases. The etiology of HCM includes over 1400 mutations in at least 11 genes. Of these mutations, those in the beta-cardiac myosin heavy chain (MYH7) and cardiac myosin-binding protein C (MYBPC3) genes are the most frequent, followed by those in the cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), and alpha-tropomyosin (TPM1) genes. Genetic testing allows the assessment of genotype–phenotype correlations. Classification of dilated cardiomyopathy Clinical manifestations of HCM caused by mutations in TNNT2 often begin near adolescence, while mutations in MYBPC3 typically trigger HCM in middle age. MYBPC3 mutation carriers develop left ventricular systolic dysfunction less frequently than nonMYBPC3 mutation carriers. Comprehensive analyses of genetic information using next-generation sequencing will provide new insights into the genetic basis of the observed phenotypes and prognosis. Recent multi-omics studies, including epigenomic, and transcriptomic analyses have shown that nongenetic factors are also associated with the clinical phenotype of cardiomyopathy. Cardiomyopathy has long been classified based on morphological characteristics; multi-omics analyses can be a standard tool for the assessments of cardiomyopathy. Disease Modeling for specific mutations using iPSC RNA-binding motif protein 20 (RBM20) A family with inherited dilated cardiomyopathy (DCM) was found to have a specific change in RBM20 The induced pluripotent stem cell (iPSC) platform was used to make heart cells (cardiomyocytes) to understand how the mutation leads to DCM. The platform also shows that retinoic acid could be a therapy to increase levels of RBM20 to treat DCM. Phenome-wide association studies (PheWAS) Allows better characterization of human genome–phenome relationship. PheWAS has the advantage of identifying genetic variants with pleiotropic properties, either good or bad. Individuals with SNV in interleukin 6 receptor (IL6R) gene are at reduced risk for aortic aneurysms PCSK9 missense variant was found to be associated with reduced risk for ischemic stroke, not associated with increased risk for diabetes. Elevated lipoprotein(a) [Lp(a)] and familial hypercholesterolemia (FH) are inherited disorders that are associated with increased coronary artery disease (CAD) risk. Lp(a) has been known to be elevated among patients with FH. Lp(a) levels are elevated in patient with clinical diagnosis of FH based on higher frequency of LPA genotypes leading to elevate LDL cholesterol, premature CVD, family history of CVD, thereby increasing the likelihood of being diagnosed as FH. Any Questions ?