Genetic Cardiac Diseases Research Articles

Pharmacological approaches to regenerative strategies for the treatment of cardiovascular diseases

Cardiovascular diseases are a group of multifactorial and complex debilitating diseases facing limitations in classical pharmacology. Instead of drug-targeting the consequences, the origin of the disease (i.e. cardiomyocytes degeneration) represents a better although challenging target. Indeed, the human heart is not or poorly able to regenerate. The loss of cardiomyocytes, occurring in many ischemic or genetic cardiac diseases, replaced by fibroblasts leads to a lower response of the myocardium to the contractile demand. Following a transient compensatory hypertrophic phase, and despite the intervention of pharmacological agents to limit the contractile demand, including beta-adrenoceptors blockers or inhibitors of the conversion enzyme, the contractile force developed reaches a limitation dropping the myocardium into a failing stage. Thus, myocardial regeneration has been envisioned using 'pharmacological' agents, genes, or stem cells. For the past decade, both gene therapy and more recently cell therapy have been tested in clinical trials to relieve some aspects of heart weakness or to compensate myocardial degeneration. Protein-based and miRNA-based regenerative therapies are also emerging from experimental animal studies. This review brings an update on the most recent research strategies to regenerate the diseased myocardium. The remaining challenges of gene-based, cell-based, or protein-based therapies to relieve heart failure are discussed.

Mutation of junctophilin type 2 associated with hypertrophic cardiomyopathy

Junctophilin subtypes, designated as JPH1 approximately 4, are protein components of junctional complexes and play essential roles in cellular Ca2+ signaling in excitable cells. Knockout mice lacking the cardiac-type Jph2 die of embryonic cardiac arrest, and the mutant cardiac myocytes exhibit impaired formation of peripheral couplings and arrhythmic Ca2+ signaling caused by functional uncoupling between dihydropyridine and ryanodine receptor channels. Based on these observations, we hypothesized that mutations of JPH2 could cause human genetic cardiac diseases. Among 195 Japanese patients (148 index cases and 47 affected family members) with hypertrophic cardiomyopathy (HCM), two heterozygous nonsynonymous nucleotide transitions, G505S and R436C, were newly found in JPH2. When Fisher's exact test was used to compare index cases with HCM to unrelated Japanese healthy controls in the frequencies of mutant alleles, only the G505S mutation showed statistical significance (4/296 HCM patients and 0/472 control individuals, P=0.022). This result was still significant after Bonferroni's correction for multiple comparisons (P=0.044). To the best of our knowledge, this is the first report on JPH2 mutation associated with HCM.

Molecular biological approaches to genetic cardiac diseases

Medical genetics has been revolutionized by the ability to analyze and manipulate DNA, the raw material of genes. Because of the importance and volume of the medically important advances being made in this arena every physician needs to have a firm grasp of the concepts and methods involved in these studies. As the accompanying articles in this issue demonstrate, pediatric cardiologists are no exception. In this review we will describe some of the important and current methods used to analyze DNA in a genetic context and outline the techniques used to characterize the products of genes identified as abnormal by genetic analysis.