Cardiomyopathy

WHAT IS CARDIOMYOPATHY? The word cardiomyopathy is cardio-, relating to the heart, and -myopathy, a disease of muscle tissue. This heart disease affects almost 1 out of every 500 Americans, making it a relatively common inherited disease affecting all age groups. The different variations of the disease affect the heart in many different ways whether it be a stretching, stiffening, thickening, or breaking down of the myocardium.

WHAT ARE THE TYPICAL SYMPTOMS? The overarching symptoms include a shortness of breath (dyspnea), chest pain, palpitations, light headedness, fatigue, and swelling, depending on the type of cardiomyopathy.

ARE THERE DIFFERENT TYPES OF CARDIOMYOPATHY? There are a myriad of types of cardiomyopathy with even more slight variations off of each type. The symptoms are relatively similar amongst them but the way the heart is affected is quite different.

HYPERTROPHIC CARDIOMYOPATHY (HCM) is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric. The myocardium becomes excessively thick, usually in interventricular septum and there becomes a myocardial disarray where the cells in the heart are not arranged in a particular order. This type of cardiomyopathy is known to be caused by mutations in genes encoding sarcomeric proteins, which are components of the contractile machinery of the heart muscle. A quarter of HCM cases are caused by mutations in MYH7, which encodes the cardiac beta (β)-myosin heavy chain protein, a major component of the thick filament in the sarcomere. While about a third of the cases are caused by mutations in MYBPC3 , which in turn encodes for cardiac myosin binding protein C that associates with the thick filament, thereby provides structural support as well as regulates muscle contractions.

DILATED CARDIOMYOPATHY is characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. This disease causes the cardiac muscle to become stretched out in at least one chamber of the heart, therefore, the heart is unable to pump blood as efficiently as usual and chambers become more stretched over time. This disease can be caused by mutations in many different genes that encode components of various cellular compartments and pathways. Among these genes are ACTN2that encodes alpha-actinin-2, which anchors actin to a variety of intracellular structures, and DES that codes for desmin protein, which is important to help maintain the structure of sarcomeres. In addition, mutations in MYBPC3 and MYH7 are also found in patients with dilated cardiomyopathy, as well as mutations in TNNT2 andTNNI3, responsible for producing cardiac troponin T and cardiac troponin I, respectively, that make up the troponin protein complex in cardiac muscle cells. This complex associates with the thin filament of the sarcomeres and controls muscle contraction and relaxation by regulating the interaction of the thick and thin filaments.

ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY is a congenital heart disease characterized by infiltration of adipose and fibrous tissue into the right ventricle and loss of myocardial cells, resulting in ventricular and supraventricular arrhythmias. Part of the myocardium breaks down over time, increasing the risk of an abnormal heartbeat (arrhythmia) and sudden death. Therefore, strenuous exercise can put individuals at a higher risk. The PKP2 gene produces plakophilin 2 which is responsible for creating desmosomes which form junctions that attach cells to one another. Desmosomes provide strength to the myocardium and are involved in signaling between neighboring cells. If desmosomes are not working properly, cells of the myocardium can detach from one another and die. Damaged myocardium is replaced by fat and scar tissue causing the walls of the right ventricle to become stretched out.

RESTRICTIVE CARDIOMYOPATHY is a heart disorder characterized by impaired filling of the ventricles with reduced diastolic volume, in the presence of normal or near normal wall thickness and systolic function. The heart muscle is stiff and cannot fully relax after each contraction. Impaired muscle relaxation causes blood to back up in the atria and lungs, which reduces the amount of blood in the ventricles. The TNNT2 gene produces cardiac troponin T which makes up troponin protein complex in cardiac muscle cells. It associates with the thin filament of sarcomeres and also controls muscle contraction and relaxation by regulating the interaction of the thick and thin filaments.

LEFT VENTRICULAR NONCOMPACTION is a disease due to an arrest of myocardial morphogenesis. It is characterized by a hypertrophic left ventricle with deep trabeculations and with poor systolic function, with or without associated left ventricular dilation. The MYH7 gene is affected as well as the TPM1 which produces Alpha-tropomyosin, vital for calcium sensitivity.

RELATED RESEARCH IN THE FAIRBROTHER LAB

The Fairbrother lab is interested in studying mutations in cardiomyopathy genes that disrupt pre- RNA splicing. The lab has developed high-throughput techniques screened over 5,000 disease causing mutations, including mutation known cardiomyopathy genes such as MYH7, TNNT2, (...) for their effects in RNA splicing. 33.4% were found to cause a defect in splicing, which lead to defective proteins that are responsible for the contraction, calcium sensitivity, and connections in the heart. By engineering mutations into artificial genes which are used in the splicing assay both in vivo and in vitro. For the in vivo assay, the mutant exon, and its wildtype counterpart, is paired with both a CMV promoter exon and a Poly A binding protein. Each three exon minigene is then injected into a pool of immortalized cell line. Once the RNA is recovered, it is converted into cDNA through a process with reverse transcriptase. For the in vitro assay, the mutant and wildtype exon is engineered to form a two exon minigene that is transcribed in vitro into RNA and then incubated in a cell extract. Then, RNA is extracted, and consequently converted into cDNA. Both the in vitro mutant and wildtype cDNA and the in vivo mutant and wildtype cDNA were then sequenced. Through this process, allelic imbalances in splicing efficiency can be discovered. For more information about the research being done in the Fairbrother lab, click here .