Effect of Losartan on Left Ventricular Diastolic Function in Patients With Nonobstructive Hypertrophic Cardiomyopathy

Araújo, Abelardo; Arteaga, Edmundo; Ianni, Bárbara Maria; Buck, Paula; Rabello, Rogerio; Mady, Charles

doi:10.1016/j.amjcard.2005.07.065

Cited by 75 publications

(48 citation statements)

References 21 publications

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“…The primary HCM-causing genetic substrate was not reported in either the Japanese 32,34 or the Brazilian 33 studies. Furthermore, in previous reports, the dose of study drug was lower 32,34 or the follow-up was shorter 33 than in the present study. This suggests that higher doses of AT1-R antagonist for a longer time may be required to decrease the magnitude of LV hypertrophy.…”

Section: Angiotensin II Blockade In Hcmcontrasting

confidence: 43%

“…Finally, in contrast to the present study, the open, non-placebo-controlled design of previous studies may hamper interpretation of results. 32,33 Nevertheless, these findings suggest that AT1-R blockade has the potential to attenuate myocardial fibrosis and hypertrophy, two major predictors of sudden cardiac death in patients with HCM.…”

Section: Angiotensin II Blockade In Hcmmentioning

confidence: 94%

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

Pěnička

Gregor

Kerekes³

et al. 2009

The Journal of Molecular Diagnostics

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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...

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Section: Angiotensin II Blockade In Hcmcontrasting

confidence: 43%

Section: Angiotensin II Blockade In Hcmmentioning

confidence: 94%

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

Pěnička

Gregor

Kerekes³

et al. 2009

The Journal of Molecular Diagnostics

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“…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.…”

Section: Signalingmentioning

confidence: 99%

Disease Pathways and Novel Therapeutic Targets in Hypertrophic Cardiomyopathy

Ashrafian

McKenna²,

Watkins³

2011

Circulation Research

154

135

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As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is principally a disease of the sarcomere. At the biophysical level, myofilament mutations generally enhance Ca 2+ sensitivity, maximal force production, and ATPase activity. These defects ultimately appear to converge on energy deficiency and altered Ca 2+ handling as major common paths leading to the anatomic (hypertrophy, myofiber disarray, and fibrosis) and functional features (pathological signaling and diastolic dysfunction) characteristic of HCM. In this review, we provide an account of the consequences of HCM mutations and describe how specifically targeting these molecular features has already yielded early promise for novel therapies for HCM. Although substantial efforts are still required to understand the molecular link between HCM mutations and their clinical consequences, HCM endures as an exemplar of how novel insights derived from molecular characterization of Mendelian disorders can inform the understanding of biological processes and translate into rational therapies.

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“…This must be considered a pilot study, and increasing the population size is necessary to draw confident conclusions regarding the correlation of AT1-R blockade and genetic mutations involved in HCM. The hypothesis of a "genetic basis" as the explanatory factor for the conflicting results in AT1-R blockade on HCM progression still remains speculative, particularly because the causative genetic mutations identified here were not examined in the previous studies, 14,16,15 making the comparison between studies rather problematic.…”

Section: As Recently Stated By Elliott and Spirito "The Prevention Omentioning

confidence: 87%

Genes, Geography and Geometry

Kaludercic

Reggiani

Paolocci

2009

The Journal of Molecular Diagnostics

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As recently stated by Elliott and Spirito, "the prevention of premature death from ventricular tachyarrhythmia, heart failure and stroke remains a major aim of clinical management in what is now called hypertrophic cardiomyopathy."1 Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, the first myocardial affliction for which a genetic basis was identified and, in essence, a disease of the contractile sarcomeric proteins. The stigmata of the disease are myocardial hypertrophy, often asymmetric and with any possible diffuse or segmental pattern of left ventricle (LV) thickening, and impaired LV contractile and diastolic function. HCM can be classified as obstructive or non obstructive. In the 25% of HCM patients with LV outflow tract obstruction, there is the presence of a dynamic ventricular gradient. A pronounced LV outflow tract obstruction directly correlates with the severity of the clinical manifestations while adversely impacting the prognosis. 2HCM results from excessive cardiac growth, increased number of fibroblasts with secretion of collagen (fibrosis), and disruption of the characteristic cell-to-cell alignment of the sarcomere and myocyte. Electrical instability (ie, atrial and ventricular arrhythmias) is another prominent feature of HCM and a leading cause of death, particularly in young athletes.3 Although HCM is a relatively benign syndrome in adult populations, with an annual frequency of sudden cardiac death (SCD) of 0.5% to 1%, HCM still remains the most common cause of death among children and adolescents (1% to 2%). 4 Early age of onset, family history of SCD, malignant arrhythmias and exercise-induced hypotension, in addition to specific genetic mutations, all contribute to a higher risk for SCD.5,6 As a matter of fact, "the major clinical challenge is the identification of the small number of individuals who are prone to serious complications and rapid disease progression." 2 Typical clinical manifestations of HCM include chest pain, exertion-related dyspnea (exercise intolerance), palpitations and, less frequently, syncope. However, HCM is clinically variable, with some patients remaining asymptomatic throughout their lifetime, while others experience the most serious complications. This heterogeneity is likely one of the major reasons for the complexity of HCM management. Unfortunately, SCD is quite often the presenting manifestation in young individuals. Current treatments focus on relieving the symptoms of HCM, treating arrhythmias (ie, atrial fibrillation and nonsustained ventricular tachycardia) that occur commonly in HCM, and, foremost, preventing SCD. These interventions include changes in lifestyle (ie, diet and exercise) and pharmacological tools such as ␤-blockers, Ca 2ϩ channel blockers and diuretics. The implantation of cardiac defibrillators is also a valid option, particularly for those patients that are at the highest risk for sudden death.HCM is caused by mutations in one of a number of genes. Approximately 450 different mutations have been discovered in gene...

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Effect of Losartan on Left Ventricular Diastolic Function in Patients With Nonobstructive Hypertrophic Cardiomyopathy

Cited by 75 publications

References 21 publications

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

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

Disease Pathways and Novel Therapeutic Targets in Hypertrophic Cardiomyopathy

Genes, Geography and Geometry

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