ABSTRACT
Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous genetic disorder characterized by peripheral muscular weakness often associated with dilated cardiomyopathy. We characterize clinically a large family with a mutation in FHL1 gene (p.Cys255Ser). Penetrance was 44%, 100% for males and 18% for females. The heart was the main organ involved. Affected adult males had mild hypertrophy, systolic dysfunction and restriction with non-dilated ventricles. Carriers had significant QTc prolongation. The proband presented with resuscitated cardiac arrest. There were two transplants. Pathological study of explanted heart showed fibrofatty replacement and scarring consistent with arrhythmogenic cardiomyopathy and prominent left ventricular trabeculations. Myopathic involvement was evident in all males. Females had no significant neuromuscular disease. Mutations in FHL1 cause unclassifiable cardiomyopathy with coexisting EDMD. Prognosis is poor and systolic impairment and arrhythmias are frequent. Thrombopenia and raised creatine phosphokinase should raise suspicion of an FHL-1 disorder in X-linked cardiomyopathy.
Subject(s)
Arrhythmias, Cardiac/genetics , Cardiomyopathy, Dilated/genetics , Intracellular Signaling Peptides and Proteins/genetics , LIM Domain Proteins/genetics , Muscle Proteins/genetics , Muscular Dystrophy, Emery-Dreifuss/genetics , Mutation , Adolescent , Adult , Aged , Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/pathology , Arrhythmias, Cardiac/surgery , Biomarkers/blood , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Dilated/surgery , Child , Child, Preschool , Creatine Kinase/blood , DNA Mutational Analysis , Female , Gene Expression , Heart Transplantation , Humans , Male , Middle Aged , Muscular Dystrophy, Emery-Dreifuss/complications , Muscular Dystrophy, Emery-Dreifuss/pathology , Muscular Dystrophy, Emery-Dreifuss/surgery , Myocardium/metabolism , Myocardium/pathology , Pedigree , Sex Factors , Thrombocytopenia/physiopathology , Ventricular RemodelingABSTRACT
Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y(12). It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.