Familial dilated cardiomyopathy secondary to dystrophin splice site mutation.

BACKGROUND: Idiopathic dilated cardiomyopathy (DCM) encompasses a heterogeneous group of disorders, posing significant diagnostic challenges. Genetic etiologies underlie an important subset of DCM, including 20 genes and 5 X-linked disorders to date. We report a family with a rare dystrophin gene alteration, identified after evaluation of asymptomatic children whose extended family history included cardiomyopathy, premature cardiac death, or cardiac transplantation. METHODS AND RESULTS: Record review, clinical evaluations, and DNA samples were obtained from members of a 5-generation pedigree with early onset DCM. Five of 6 affected males experienced death or cardiac transplant in their second or third decades. No affected individuals had skeletal muscle weakness before acute cardiac decompensation. Dystrophin gene analysis of an affected family member revealed sequence alteration at the conserved 5' splice site of exon 1 of the muscle-specific isoform of dystrophin (IVS1 +1 G>T) and co-segregated with cardiac disease in this family. CONCLUSIONS: Young males presenting with apparent isolated cardiomyopathy or acute myocarditis may harbor dystrophin mutations without overt skeletal muscle pathology. The etiology of familial risk was not evident in this pedigree before retrospective cardiovascular genetics assessment, highlighting ongoing diagnostic challenges and limitations of standardized screening panels (which do not include dystrophin) in patients with "idiopathic" DCM.

Heparin-induced thrombocytopenia: a common complication in cardiac transplant recipients.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an idiosyncratic complication of heparin therapy triggered by the development of immunoglobulin G (IgG) antibodies to platelet factor 4 heparin. It typically results in a 50% decrease in platelet count. Paradoxically, although bleeding is rare, there is a high risk of venous or arterial thrombotic events. Given that many patients awaiting transplantation are exposed to heparin for prolonged periods, we sought to determine the frequency of HIT and its consequences among patients before and after cardiac transplantation. METHODS: We reviewed retrospectively the clinical, pathologic, and laboratory databases for all patients who underwent heart transplantation at our institution between January 1, 1998, and December 31, 2000. An enzyme-linked immunoabsorption assay (ELISA) that detected IgG, IgA, and IgM antibodies directed against platelet factor 4 heparin complex confirmed the diagnosis of HIT. We analyzed bleeding and thrombotic complications and determined the influence of HIT on post-transplant outcomes. RESULTS: An assay for HIT antibody was performed before or after transplantation in 26 of 46 patients (46% of the entire cohort). In all cases, the clinical indication for testing was thrombocytopenia. Among patients screened, HIT antibody was detected in 11 patients (39%); HIT developed in 10 of 11 patients before transplantation. The mean platelet count at diagnosis was 88,000 +/- 22,000/mm(3). Heparin-induced thrombocytopenia with thrombosis syndrome developed in 5 of 11 patients (45%). Manifestations included splenic and renal infarctions, renal artery occlusion, coronary artery embolism with myocardial infarction, pulmonary embolism, and femoral and jugular venous occlusions. Alternative pre-operative anti-coagulation included lepirudin (n = 7), argatroban (n = 1), dalteparin (n = 1), and abciximab (n = 1). Two deaths occurred in the HIT-positive group; neither bleeding nor thrombosis caused either death. Actuarial 36-month survival did not differ between HIT-positive and HIT-negative cohorts (78% and 79%, respectively). CONCLUSION: Heparin-induced thrombocytopenia is a frequent complication among patients hospitalized for heart failure who are awaiting heart transplantation. Timely HIT-antibody screening and the use of alternative forms of systemic anti-coagulation may permit successful transplantation with intermediate survival rates comparable to those of HIT-negative recipients.