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Age-related changes in cardiomyopathic phenotype in patients with barth syndrome
With current treatment options for BTHS cardiomyopathic phenotype focused predominantly on alleviating symptoms, Dr Hani N. Sabbah, Director of Cardiovascular Research at Henry Ford Health, explores the potential of more targeted treatment approaches. Barth syndrome (BTHS) is a rare, X-linked disease caused by defects in the TAFAZZIN gene encoding an acyltransferase responsible for the remodeling/maturation of cardiolipin (critical to mitochondrial structure/function).(1) The most common clinical manifestation of BTHS is cardiomyopathy (~90% of BTHS patients) with a wide range of phenotypical presentations.(2,3) Mechanisms contributing to BTHS cardiomyopathy pathophysiology include abnormal mitochondrial structure/function,(4) defective mitochondrial calcium uptake,(5) a mismatch between ATP supply and demand,(6) and altered lipid/glucose metabolism.(7) The BTHS cardiomyopathic phenotypes appear to evolve with advancing age, which may be useful in treatment selection.

Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria. ; Stealth BioTherapeutics; NIH (NHLBI) [R01 HL123647, R15 HL122922]; NIH [R01 HL123647, R15 HL122922, NIA R01 AG049762, NHLBI R01 HL131458, R01HL126928, R01HL107715, R01 AT008375]; European Union; European Commission [FP7-242209-BIOSTAT-CHF] ; The roundtable discussion in Stresa, Italy, was organized by Logica Med LLC and funded by an unrestricted grant from Stealth BioTherapeutics. We thank Fumiko Inoue (Logica Med) for her help in organizing the roundtable meeting. The authors also acknowledge BioCentric, Inc. for their assistance with developing previous versions of the manuscript Figures. D.A.B. has received research grants from the NIH (NHLBI R01 HL123647 and R15 HL122922) and Stealth BioTherapeutics. B.L.S. is supported by research grants from the NIH (NIA R01 AG049762, NHLBI R01 HL131458, R01HL126928, and R01HL107715) and Stealth BioTherapeutics. S.R.S. is supported by grants from the NIH (R01 HL123647, R15 HL122922, and R01 AT008375). J.B. has received research support from the NIH and the European Union. A.A.V. is supported by a grant from the European Commission (FP7-242209-BIOSTAT-CHF).