Precision Medicine and Generation of Human Cardiomyocytes from iPSCs
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Advances in Application of iPSC-derived Cardiomyocytes for Future Medicine
-Modeling Inherited cardiomyopathy with human iPSC-derived cardiomyocytes
The advent of iPS cell technology and improvements in protocols for cardiomyocytes differentiation open the door to using iPSC-CMs platform for disease modeling and toxicological assays in various cardiovascular diseases. To data, one of the most successful area in research application of iPSC-CMs is the development of the disease model of inherited cardiovascular disease.
For example, hypertrophic cardiomyopathy (HCM), which is a common genetic cardiomyopathy characterized by marked hypertrophy of
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More recently, we have shown the usefulness of the iPSC-CM technology to understand molecular mechanism in cardiac developmental defects. Left ventricular non-compaction (LVNC) is a relatively common form of cardiomyopathy in children, and is typically characterized by prominent trabeculations with deep recesses. We generated iPSC-CMs from LVNC patients carrying a stop-gain mutation in the TBX20 gene (Try317*), and demonstrated that LVNC-iPSC-CMs recapitulate the proliferative defects associated with the disease. We found that TGF-β signaling pathway is abnormally activated due to functional disturbance of TBX20 in LVNC-iPSC-CMs, and inhibition of TGF-β signaling or TBX20 mutation correction by transcription activator-like receptor nuclease (TALEN) rescued the proliferative defect in LVNC-iPSC-CMs.
Recent advances in genome-editing tools, such as TALEN and CRISPR (clustered regularly interspaced short palindromic repeat), have father expand the potential application of iPSC-CM technology for precision medicine. Currently, disease diagnosis and prognosis in asymptomatic individuals carrying a potential disease-causing mutation mainly rely on careful monitoring of biomarkers or heart function, and their family history. However, this approach sometimes requires long-term medical follow-up, leading a
Hypertrophic cardiomyopathy is an inherited disease that affects the cardiac muscle of the heart, causing the walls of the heart to thicken and become stiff. [1] On a cellular level, the sarcomere
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According to the WHO, cardiovascular diseases have been the leading cause of death globally claiming 17 million lives a year, more deaths than all cancer combined (Chiu and Radisic, 2013). Cardiovascular disease is responsible for a preponderance of health problems and its impact is expected to grow further as the population ages. In the UK, NHS spends about £7.74 billion as the expenditure to deal with cardiovascular diseases (Barton et al., 2011). Cardiovascular disease in the form of myocardial infarction has become the principle cause of death in developed countries, accounting for nearly 40% of all deaths (http://www.bhf.org.uk/). Congenital heart defects, which occur in nearly 14 of every 1000 new-born children, is another tragic fact that baffles medical industry (http://www.heart.org/). About 61 million Americans (almost one-fourth of the population) live with cardiovascular diseases, such as coronary heart disease, congenital cardiovascular defects, and congestive heart failure.
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Critical Congenital Heart Defects are abnormalities of the heart structure that are present at birth. These occur because of incomplete or abnormal development of the fetus’ heart. These defects can cause severe mortality within the newborn stage (Goldstein, 2013, p.1). Several are known to be linked to genetic disorders such as Down syndrome and others are thought to be linked to environmental factors that women can be exposed to while pregnant. The cause of most CCHD’s is unknown.
Cardiomyopathy is a disease of the heart muscle. It is where the ventricular structure is impaired. The heart muscle
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TOF is a CHD which means the abnormal development of the heart occurred during gestation .A normal heart consists of four chambers of cardiac muscle cells, four heart valves, an electrical pathway, and its own blood supply. The chambers are the Right Atrium (RA) , Right Ventricle ( RV), Left Atrium,(LA) , and the Left Ventricle ( LV). The blood flows from the Vena Cava to the RA thru the Tricuspid Valve to the RV. It then gets ejected thru the Pulmonary Valve into the Pulmonary Artery, and on into the lungs. It returns to the LA, goes thru the Mitral Valve into the LV, and then is ejected thru the Aortic Valve into the aorta and onto systemic circulation. TOF is identified by four atypical finding within the heart.
Hypertrophic cardiomyopathy (HCM) is a primary disease of the myocardium (the muscle of the heart) in which a portion of the myocardium ishypertrophied (thickened) without any obvious cause. It is perhaps best known as a leading cause of sudden cardiac death in young athletes.[7] The occurrence of hypertrophic cardiomyopathy is a significant cause of sudden unexpected cardiac death in any age group and as a cause of disabling cardiac symptoms. Younger people are likely to have a more severe form of hypertrophic cardiomyopathy.
These separate forms of the condition come with distinct traits that vary from one to the next. Dilated cardiomyopathy, “The most common form, this occurs when the muscle fibers of one or both pumping chambers are weak and unable to contract normally” (“Understand Pediatric” 1). Which means that the heart beats abnormally due to lack of blood flow. Often with DCM the heart is weak and fails because it cannot sufficiently pump blood throughout the body (“Understanding Pediatric” 1). The article on “Understanding Pediatric Cardiomyopathy” states that hypertrophic cardiomyopathy is the second most common form. HCM has a few characteristics that can be mistaken for dilated cardiomyopathy. Thick and stiff muscles may stop the heart from contracting properly, which may narrow the passageways for blood to move out of the heart (“Understanding Pediatric” 1). So, the muscles within the heart thicken to try and help blood flow. In an advanced form of hypertrophic cardiomyopathy, there is a chance that the muscles may thin to try to help the poor pumping action (“Understanding Pediatric” 1). When HCM tries to help the body it, in itself, can cause failure. A
Hypertrophic cardiomyopathy is a genetic disease that causes the heart muscle to become thickened (Maron, 2015). According to the Mayo Clinic (n.d.), hypertrophic cardiomyopathy is a genetic disorder; however, environmental or lifestyle factors may influence how and when the disease appears in individuals.
Pathological cardiac hypertrophy is associated structural remodeling which can include cardiomyocyte growth, fibrosis (formation of collagen fibril connective tissue) and angiogenesis (formation of new blood vessels).
Hypertrophic Cardiomyopathy is also known as HCM. It is a genetic condition in which the myocardium or heart muscle in the left ventricle is thickened. HCM cannot be identified by a single complaint or symptom as it is different for every person that it affects. This disease not only causes left ventricle hypertrophy but can also cause ventricle stiffness, mitral valve changes, and other cellular changes.
Metabolic syndrome is a group of disorders that predisposes to the cardiovascular disorders and constituted a significant risk for coronary heart disease, however, its effect on gene expression pattern is unclear. The considerable evidence demonstrated that genetic factors predispose to the cardiovascular complications. Metabolic syndrome significantly alters cardiac gene expression profile which may be involved in the development of cardiovascular disease.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) (1) is an inherited disease characterized by the progressive replacement of the myocardium by adipose and fibrous tissue (2) that predisposes to the development of ventricular tachycardia (VT) and to sudden cardiac death (SCD). This condition was described three decades ago, when fibro-fatty infiltration in the right ventricle was considered its pivotal indicator (3,4). It later became clear that the ARVC is mainly caused by mutations in the genes encoding for desmosomal proteins (1). This helped unveil that the disorder is often associated with biventricular manifestations (5) and the term "arrhythmogenic cardiomyopathy" has also been proposed (1). The unmet need in the management