The annual incidence of sudden cardiac death in the United States is in the range of 180,000 to 250,000 per year and unlikely to subside in the future with the increase in the age of the population as well an increase in cardiac risk factors such as diabetes mellitus and obesity. Alterations in ionic fluxes comprise the cellular basis for the arrhythmias that underlie sudden arrhythmic deaths. These alterations usually lead to an increase in myocardial cell repolarization time and an increase in the duration of the action potential. This corresponds to an increase in the QT interval on a surface electrocardiogram. Prolongation in the QT interval has been noted in diverse conditions including myocardial ischemia, in response to administration of commonly used drugs such as erythromycin and haloperidol (as an unintended side-effect), and as a congenital condition.
Many genetic causes for long QT syndrome (LQTS) have been identified, with the majority of mutations seen in genes that encode for three main cardiac ion channels (KCNQ1, KCNH2 and SCN5a). Unfortunately there are no current therapies for the treatment of LQTS that address the underlying mechanistic problem, namely prolongation of the action potential and myocardial repolarization. Additionally, most anti-arrhythmic medications prolong myocardial repolarization and drugs that shorten QT interval are rare and have very small effects. Thus medications that alter ion channel function that lead to shortening of the action potential and myocardial repolarization would be a novel class of agents in treating patients with genetic and acquired LQTS.
Zebrafish recapitulate several key aspects of human myocardial repolarization and have a long history of being used successfully for high-throughput screening of drugs. Recently it was shown that zebrafish models of acquired LQTS as well as genetic LQTS can be used for screening small molecules that can shorten myocardial repolarization, thereby rescuing the zebrafish LQTS. In particular the breakdance (bkd) mutant carries a mutation in the KCNH2 gene with observed 2:1 heart block due to prolonged action potential and phenocopies human LQT2. High throughput screening for small molecules that rescue the phenotype of bkd has been successfully conducted.
In addition, cardiovascular disease is responsible for 600,000 deaths per year in the United States, making it the leading cause of death in both men and women. The total annual estimated costs associated with coronary artery disease alone amount to $109 billion.
Heart failure (HF) is a clinical syndrome of growing prevalence that can either be acquired, for example after myocardial infarction or pressure overload as in hypertension and valvular stenosis, or can be genetic due to de novo or inherited mutations. While there are evidence-based therapies for systolic HF, there has not been a new class of medications approved for HF in approximately a decade. Thus there is a substantial unmet clinical need for novel therapeutic approaches in HF.
Cardiomyopathies are a group of diseases affecting heart muscles, also known as the myocardium. Dilated cardiomyopathy weakens the heart and affects its ability to pump enough blood to the organs. This can lead to heart failure and death, as well as problems elsewhere in the body. Approximately 25-30% of heart failure may be due to genetic mutations that can occur de novo in affected individuals or can be familial and inherited. Although the genetic causes of dilated cardiomyopathy (DCM) are diverse, the most common genes affected encode structural components of the cytoskeleton and/or sarcomere. Treatment for dilated cardiomyopathy is limited, and includes drug treatment to alleviate symptoms, implantation of devices, and heart transplants. However these may have unwanted side effects or be ineffective. Accordingly, there is a need for further treatment options to deal with dilated cardiomyopathy.
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USPTO Backgrounds