Outcome-targeted Therapy: Principle and Outcome Evaluation: Clinical Study and Phenotype-genotype Correlation

Dilated cardiomyopathy (DCM) is the most common childhood cardiomyopathy and is associated with significant early morbidity and mortality. About half of patients die or require heart transplantation within 5 years of diagnosis. The survival advantage from transplantation is limited, particularly in DCM infants.The medical therapy for DCM with heart failure includes anti-congestive medications and antiplatelet therapy. Those who fail to improve within the first year of diagnosis usually deteriorated even upon aggressive anti-congestive medications. Investigators have conducted precision-medicine-based approach to provide strategic approach as drug repurposing to identify new treatments. Investigators have identified the beneficial effects from a statin, simvastatin, to restore the cardiac contractility in the human induced pluripotent stem cell lines derived from a DCM proband and the proband's father. The mutant mouse consequently confirmed the beneficial effects. The initial experience in the proband is promising. The proband was diagnosed as DCM with severe heart failure during infancy. Family screening identified that the proband's father had dilated left ventricle (LV) and low LV ejection fraction (LVEF). Genetic examination of this DCM family revealed that the proband and the proband's father had heterogeneous missense mutation. About 2 years after the disease onset, participants growth was slow, the LVEF remained poor and the NT-pro BNP level was high under aggressive anti-congestive medications. Because of the beneficial effects of simvastatin from in vitro study and in vivo animal study, off-label use of simvastatin was initiated after obtaining the parents' agreement. Participants general condition and cardiac condition 4 years after the disease onset and 1.5 years after the simvastatin therapy improved without adverse effects. The LVEF increased from 17.5% to 39.2% and the NT-pro BNP level dropped from 1200 to 363 pg/ml. Simvastatin is effective in lowing LDL and cholesterol, thereby to improve the outcome of patients with coronary arterial disease, familiar hypercholesterolemia, etc. For children, though the dosage range and the indication remain unclear, it had been used in children with various diseases. Simvastatin had been given in a small cohort of adult DCM. Patients treated with simvastatin had a lower New York Heart Association functional class compared with those receiving placebo. The LVEF also improved in the simvastatin group. This clinical trial is to find out if simvastatin will benefit the cardiac function of DCM patients.

Inclusion criteria

Patients diagnosed as dilated cardiomyopathy, classified as NYHA functional class II or III and still have a low left ventricular ejection fraction (LVEF) (LVEF < 45% and the Z score of the LV end-diastolic diameter > 2.0) will be enrolled, if they have normal or high level of cholesterol and triglyceride and fulfill any of the following criteria:

• Patients who have already received anti-congestive medications for at least three months and still have poor LV function (LVEF < 45% and the Z score of the LV end-diastolic diameter > 2.0).
• Patients who have persistent or even worsening heart failure after one month of anti-congestive medications.
• Patients who have positive family history of dilated cardiomyopathy and have received anti-congestive medications for one month.
• Patients or their parents must sign an informed consent form.

Exclusion criteria

Patients who fulfill any of the following criteria will be excluded from the trial:

• Patients who underwent prior cardiac surgery. Those who received DCM related surgery, such as mitral valve plasy, for longer than a year are not subject to this restriction.
• Patients who had active liver / renal dysfunction.
• Concomitant use with gemfibrozil, cyclosporine, danazol, strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, erythromycin, HIV protease inhibitors, itraconazole, ketoconazole, nefazodone, posaconazole, telaprevir, telithromycin, voriconazole), or cobicistat-containing products
• Patients who are pregnant or plan to pregnancy in the period of study.
• Patients who are intolerance to simvastatin therapy.