Nevertheless, the simplicity of using injections of naked plasmid DNA into skeletal muscle tissue as an effective means to deliver a potent, secreted angiogenesis factor into ischemic peripheral vascular beds is both an exciting and encouraging finding. It is estimated that 150,000 patients per year require lower-limb amputations for ischemic peripheral vascular disease in the United States. The impressive progress being made toward the use of VEGF gene therapy for effective therapeutic angiogenesis in ischemic peripheral vascular disease is truly welcome news for clinicians faced with the task of providing care for those patients suffering from lower-limb vascular insufficiency.

The study of Sun and coworkers is important because (1) it provides additional data that HM has an inotropic and an attenuated coronary vasodilator reserve. They also provided data that support the conclusion that with dobutamine, the improvement of abnormal LV wall motion is real in many patients. (2) It emphasizes the possibility of a deleterious effect (infarction) of dobutamine in HM and thus the need for appropriate caution during its use. (3) It provides additional data that confirm that areas of perfusion-metabolism mismatch on PET imaging (HM) are associated with a reduced MBF at rest. However, their conclusions about areas of LV dysfunction with "normal" MBF in coronary artery disease are problematic; therefore, one must be extremely cautious about these conclusions on the basis of the data that are presented.

Myocardial failure has been considered to be an irreversible and progressive process characterized by ventricular enlargement, chamber geometric alterations, and diminished pump performance. However, more recent evidence has suggested that certain types of medical therapy may lead to retardation and even reversal of the cardiomyopathic process. In the failing heart, long-term neurohormonal/autocrine-paracrine activation results in abnormalities in myocyte growth, energy production and utilization, calcium flux, and receptor regulation that produce a progressively dysfunctional, mechanically inefficient heart. Interventions such as ACE inhibition and beta-blockade result in a reduction in the harmful long-term consequences of neurohormonal/autocrine-paracrine effects and retard the progression of left ventricular dysfunction or ventricular remodeling. Furthermore, in subjects with idiopathic dilated or ischemic cardiomyopathy, antiadrenergic therapy with beta-blocking agents appears to be able to partially reverse systolic dysfunction and ventricular remodeling. Although the precise mechanisms underlying this latter effect have not yet been elucidated, the general mechanism appears to be via improvement in the biological function of the cardiac myocyte. Such an improvement in the intrinsic defect(s) responsible for myocardial failure will likely translate into important clinical benefits.

Cardiomyopathy (CM) remains one of the leading cardiac causes of death in children, although in the majority of cases, the cause is unknown. To have an impact on morbidity and mortality, attention must shift to etiology-specific treatments. The diagnostic evaluation of children with CM of genetic origin is complicated by the large number of rare genetic causes, the broad range of clinical presentations, and the array of specialized diagnostic tests and biochemical assays.

The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease, Mutations in the human ether-à-go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KVLQT1, a newly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HERG mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings.