Long Term Effects of Enalapril and Losartan on Genetic Heart Disease
Long Term Effects of Enalapril and Losartan on Genetic Heart Disease
The human heart is divided into four chambers. One of the four chambers, the left ventricle,
 is the chamber mainly responsible for pumping blood out of the heart into circulation.
 Hypertrophic cardiomyopathy (HCM) is a genetically inherited disease causing an abnormal
 thickening of the heart muscle, especially the muscle making up the left ventricle. When the
 left ventricle becomes abnormally large it is called left ventricular hypertrophy (LVH). This
 condition can cause symptoms of chest pain, shortness of breath, fatigue, and heart beat
 palpitations.

 This study is designed to compare the ability of two drugs (enalapril and losartan) to
 improve symptoms and heart function of patients diagnosed with hypertrophic cardiomyopathy
 (HCM).

 Researchers have decided to compare these drugs because each one has been used to treat
 patients with other diseases causing thickening of the heart muscle. In these other
 conditions, enalapril and losartan have improved symptoms, decreased the thickness of heart
 muscle, improved blood flow and supply to the heart muscle, and improved the pumping action
 of the heart muscle.

 In this study researchers will compare the effectiveness of enalapril and losartan when given
 separately and together to patients with hypertrophic cardiomyopathy (HCM).
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease characterized by left
 ventricular (LV) hypertrophy. There is often associated LV diastolic dysfunction and
 myocardial ischemia. The severity of the LV hypertrophy, diastolic dysfunction, and
 myocardial ischemia are important determinants of clinical outcomes. Angiotensin II modulates
 cell growth and cardiac function. There is also increasing evidence that the
 renin-angiotensin system (RAS) may be present in cardiac cells, and the hypertrophic action
 of angiotensin II could therefore be mediated by circulating or locally produced hormone.
 Animal and clinical studies have demonstrated that independent of their effects on systemic
 blood pressure, ACE inhibition and angiotensin II receptor (AT1) blockade can reduce cardiac
 hypertrophy, improve LV diastolic function and myocardial ischemia. AT1 blockade may be
 preferable to ACE inhibitors because by inhibiting angiotensin II from binding to its
 receptor, the system can be turned off irrespective of the source of angiotensin II. Also,
 there may be fewer side effects due to lack of bradykinin. This is a double-blind,
 placebo-controlled study that examines the abilities of enalapril (ACE inhibition) and
 losartan (AT1 blockade), separately or in combination, to cause regression of the cardiac
 hypertrophy, and to improve LV function and myocardial perfusion in non-obstructive HCM.
INCLUSION CRITERIA

 HCM of either gender, aged 20-55 years.

 Non-dilated LV (LVIDd less than 60 mm) with LV wall thickness of greater than or equal to
 16 mm measured in any LV segment by NMR.

 Non-obstructive HCM: A LV outflow gradient of less than or equal to 30 mm Hg gradient at
 rest and less than or equal to 55 mm Hg following isoproterenol infusion to a heart rate of
 greater than or equal to 120 beats per minute at cardiac catheterization.

 New York Heart Association functional class I-III.

 Patients who have participated in the previous toxicity study may be recruited for this
 study, if they wish.

 Patients who have previously taken an ACE inhibitor or losartan could only be included in
 this study, if they have been off these drugs for a period of 6 months or longer.

 EXCLUSION CRITERIA

 Severe cardiac symptoms at rest (NYHA IV).

 LV outflow tract gradient of greater than 30 mm Hg at rest or greater than 55 mm Hg
 following isoproterenol infusion to a heart rate of greater than or equal to 120 beats per
 minute at cardiac catheterization.

 Systemic diseases (respiratory, neurologic, or locomotor) that prevent exercise testing,
 echocardiography or NMR, MUGA, thallium studies, and cardiac catheterization.

 Coronary artery disease (greater than 50% arterial luminal narrowing of a major epicardial
 vessel) or congenital cardiovascular abnormalities (e.g. ASD, VSD, coronary anomalies).

 Chronic atrial fibrillation.

 Bleeding disorder (PTT greater than 35 sec, pro time greater than 14.7 sec, platelet count
 less than 154 k/mm3).

 Anemia (Hb less than 12.7 g/dl in males and less than 11.0 g/dl in females); renal
 impairment (BUN greater than 22 mg/dl and serum creatinine greater than 1.4 mg/dl); K+ less
 than 3.3 mmol/l or greater than 5.1 mmol/l.

 Hypertension: basal systolic and diastolic pressures of greater than 160 mm Hg or greater
 than 95 mm Hg, respectively on two occasions separated by one hour of rest.

 Hypotension: basal sitting systolic arterial pressure less than 100 mm Hg confirmed 30
 minutes later.

 Must have ability to estimate LV wall thickness.

 Radiographic evidence of overt cardiac failure (pulmonary edema on chest X-ray).

 Negative urine pregnancy test.

 Pregnant or lactating female patients.

 Diminished LV systolic function (resting or exercise LV ejection fractions estimated by
 radionuclide angiography less than 50%).

 Dependence on other cardioactive drugs such as diuretics, verapamil, B-blockers, or
 antiarrhythmic drugs to control symptoms and arrhythmias.

 Negative HIV test.

 Sensitivity to ACE inhibitor e.g. angioedema.

 Must have ability to set up an outpatient monitoring system.