The Effects of Candesartan on Left Ventricular Hypertrophy and Function in Nonobstructive Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy is caused by mutations in the genes that encode sarcomeric proteins and is primarily characterized by unexplained left ventricular hypertrophy, impaired cardiac function, reduced exercise tolerance, and a relatively high incidence of sudden cardiac death, especially in the young. The extent of left ventricular hypertrophy is one of the major determinants of disease prognosis. Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. Here in a double-blind, placebo-controlled, randomized study, we show that the long-term administration of the angiotensin II type 1 receptor antagonist candesartan in patients with hypertrophic cardiomyopathy was associated with the significant regression of left ventricular hypertrophy, improvement of left ventricular function, and exercise tolerance. The magnitude of the treatment effect was dependent on specific sarcomeric protein gene mutations that had the greatest responses on the carriers of ß-myosin heavy chain and cardiac myosin binding protein C gene mutations. These data indicate that modulating the role of angiotensin II in the development of hypertrophy is specific with respect to both the affected sarcomeric protein gene and the affected codon within that gene. Thus, angiotensin II type 1 receptor blockade has the potential to attenuate myocardial hypertrophy and may, therefore, provide a new treatment option to prevent sudden cardiac death in patients with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM) is a primary cardiac disease characterized by unexplained cardiac hypertrophy and a relatively high incidence of sudden cardiac death, especially in young people.1,2 The extent of left ventricular hypertrophy is one of the major determinants of symptoms and prognosis. 3,4 Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. 5,6 Inhibition of angiotensin-converting enzyme (ACE) or the angiotensin II type 1 receptor (AT1-R) induced regression of myocardial hypertrophy in patients with hypertension or after myocardial infarction. [7][8][9] In HCM, ACE and AT1-R gene polymorphisms have been shown to be associated with severity of hypertrophy, a high incidence of atrial fibrillation and the risk of sudden cardiac death. -17Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter study to test the safety and effects of AT1-R antagonist candesartan in patients with nonobstructive HCM. We hypothesized that long-term use of candesartan would be associated with regression of left ventricular (LV) hypertrophy and improvement of LV function. Materials and Methods PatientsThis was a double-blind, placebo-controlled, randomized multicenter study. The study population consisted of 24 consecutive, genetically independent, adult (Ն18 years) patients (age 43 Ϯ 13 yrs; 46% males) with nonobstructive HCM, and normal ejection fraction (Ն60%) and sinus rhythm, who visited the participating in...

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

“…35 However, small studies showing a positive effect of RAAS inhibitors on progression of hypertrophy and fibrosis in HCM need confirmation. 36,37 Furthermore, our study was limited to five candidate polymorphisms and the role of other common genetic variants in explaining phenotypic variability among HCM patients, which may act in a mutation-specific way, merits investigation perhaps in future genome-wide association studies. Data depict mean ± SD, n (% within the particular pro-LVH score group) or median (interquartile range).…”

Disease Pathways and Novel Therapeutic Targets in Hypertrophic Cardiomyopathy

“…4,[67][68][69][70][71][72][73] Other pharmacological approaches to mitigating LVH include rapamycin (inhibiting the mammalian target of rapamycin -mTOR), which exhibits antihypertrophic properties in rodents. 74 In practice, derivatives or substitutes of such agents will likely be required because of their immunosuppressive effects.…”

“…For example, though regression of LVH may be regarded as a beneficial attribute of an HCM therapy, 3,4 in other contexts, regression of LVH may represent a detrimental prelude to ventricular dilatation. 5 Moreover, existing treatments for HCM are often applied without robust evidence, being based on underpowered studies with end-points that do not reflect the biology of the disease.…”

Genes, Geography and Geometry

“…The study conducted by Penicka and colleagues 17 in the current issue of the Journal of Molecular Diagnostics addresses these issues. These authors first hypothesized that a long-term (12 months) administration of the angiotensin II type I receptor antagonist candesartan in patients with HCM is able to reduce LV hypertrophy as well as improve LV function and exercise tolerance.…”

“…Setting aside these intrinsic limitations, the work by Penicka and co-workers 17 introduces a number of new intriguing questions and starting points for future more in-depth investigations. Half of the patients with unexplained LV hypertrophy do not have a sarcomere or sarcomere-related gene mutation.…”