A case report of recurrent transient ischaemic attacks on dabigatran for atrial fibrillation: real-world insight into treatment failure.

BACKGROUND: Non-valvular atrial fibrillation (AF) is an important risk factor for acute ischaemic stroke. There has been an increase in the use of direct-acting oral anticoagulants (DOAC therapy) in stroke prophylaxis due to their convenience and rapid action of onset. However, there is a lack of information in the literature regarding management options and possible mechanisms with the apparent failure of DOAC therapy. CASE SUMMARY: We present a clinical case of a 51-year-old man presenting with transient ischaemic attacks on a background of AF on therapeutic doses of dabigatran. His medication box suggested 100% compliance and his admission coagulation studies showed a marginally prolonged activated partial thromboplastin time and thrombin time (TT). While in hospital, our patient had supervised doses of dabigatran (150 mg b.i.d.). Despite this, his peak dabigatran level was undetectable (<40 ng/mL). With the apparent failure of therapy, he was switched to apixaban 5 mg b.i.d., which showed subsequent peak levels in the target range. DISCUSSION: There are a number of isolated case reports of DOAC failure in stroke prophylaxis and management has simply involved switching to another DOAC or warfarin. This case is unique as we have discovered undetectable levels of dabigatran providing a mechanism for failure.

Global hypercoagulability in patients with schizophrenia receiving long-term antipsychotic therapy.

BACKGROUND: Patients with schizophrenia are at increased risk of venous thromboembolism. The mechanisms underlying this association are poorly understood. AIMS: We investigated whether there is a global hypercoagulable state in patients with schizophrenia utilising the overall haemostatic potential (OHP) assay which assesses overall coagulation potential (OCP), haemostatic potential (OHP) and fibrinolytic potential (OFP). METHOD: Citrated plasma was collected for OHP assays from patients with schizophrenia on long-term antipsychotic treatment and compared with healthy age- and sex-matched controls. Time courses of fibrin formation and degradation were measured by spectrophotometry (absorption of 405nm) after the addition of tissue factor and tissue plasminogen activator to plasma. RESULTS: Ninety patients with schizophrenia (antipsychotic treatment-15.9±9.7years) and 30 controls were recruited. Patients with schizophrenia had higher rates of smoking and levels of inflammatory markers (high-sensitivity C-reactive protein and neutrophil-to-lymphocyte ratio) than controls. Whilst D-dimer, fibrinogen and platelet count did not differ between patients with schizophrenia and controls, the OCP (54.0±12.6 vs 45.9±9.1, p=0.002) and OHP (12.6±5.8 vs 7.2±3.7, p<0.001) were higher, and OFP was lower (76.6±9.8% vs 84.9±6.4%, p<0.001) in patients with schizophrenia, implying both a hypercoagulable and hypofibrinolytic state in these patients. Importantly, abnormalities in overall coagulation were independently predicted by levels of plasminogen-activator-inhibitor-1, fibrinogen, platelet count, inflammatory markers and plasma triglycerides, suggesting a multifactorial aetiology. CONCLUSION: Patients with schizophrenia have evidence of a global hypercoagulable and hypofibrinolytic state which may contribute to their increased risk of venous thromboembolism.

Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy.

BACKGROUND: The transcription factor NKX2-5 is crucial for heart development, and mutations in this gene have been implicated in diverse congenital heart diseases and conduction defects in mouse models and humans. Whether NKX2-5 mutations have a role in adult-onset heart disease is unknown. METHODS AND RESULTS: Mutation screening was performed in 220 probands with adult-onset dilated cardiomyopathy. Six NKX2-5 coding sequence variants were identified, including 3 nonsynonymous variants. A novel heterozygous mutation, I184M, located within the NKX2-5 homeodomain, was identified in 1 family. A subset of family members had congenital heart disease, but there was an unexpectedly high prevalence of dilated cardiomyopathy. Functional analysis of I184M in vitro demonstrated a striking increase in protein expression when transfected into COS-7 cells or HL-1 cardiomyocytes because of reduced degradation by the Ubiquitin-proteasome system. In functional assays, DNA-binding activity of I184M was reduced, resulting in impaired activation of target genes despite increased expression levels of mutant protein. CONCLUSIONS: Certain NKX2-5 homeodomain mutations show abnormal protein degradation via the Ubiquitin-proteasome system and partially impaired transcriptional activity. We propose that this class of mutation can impair heart development and mature heart function and contribute to NKX2-5-related cardiomyopathies with graded severity.

A randomised, placebo-controlled trial of carvedilol in early familial dilated cardiomyopathy.

BACKGROUND: Screening of asymptomatic relatives of patients with dilated cardiomyopathy (DCM) has identified a population of individuals with left ventricular dilatation and/or minimally impaired contraction who are believed to have early disease. A proportion of these individuals with early disease progress to overt cardiomyopathy, however to our knowledge there have been no studies that have examined the impact of early intervention on disease progression. METHODS: We evaluated 424 asymptomatic relatives in 110 families of probands with DCM and identified 102 individuals (24%) with suspected "early disease" (EDCM). Thirty-two EDCM subjects were randomised into a six-month placebo-controlled trial of the ß-blocker, carvedilol. Transthoracic echocardiography and plasma nt-proBNP levels were measured at baseline and repeated at six months. The primary trial endpoint was change in left ventricular end-systolic diameter after six months. Subjects completing six months of blinded trial therapy were offered open-label carvedilol and then observed over an extended period with repeated clinical evaluation and echocardiography. RESULTS: At baseline, left ventricular dimensions, systolic function and plasma nt-proBNP levels were similar in carvedilol and placebo groups. There were no significant changes observed in these parameters in either treatment group after six months, however reductions in end-diastolic diameter (% predicted) were observed in carvedilol-treated subjects (P=0.002) during an open-label median follow-up of 32 months (range: 13-56 months). CONCLUSIONS: In an asymptomatic population of individuals with EDCM, treatment with carvedilol for six months had no effect on echocardiographic left ventricular dimensions or systolic function, however longer-term treatment may reverse left ventricular remodelling (Australian Clinical Trials Registry N012605000204640).

Evaluation of left ventricular enlargement as a marker of early disease in familial dilated cardiomyopathy.

BACKGROUND: Echocardiographic screening of families with dilated cardiomyopathy has identified a subgroup of asymptomatic relatives with left ventricular enlargement (LVE). The prognostic significance of LVE in this setting is incompletely understood. METHODS AND RESULTS: We evaluated 457 asymptomatic relatives in 128 dilated cardiomyopathy families and identified 110 individuals (24%) with LVE. Serial echocardiograms in 72 untreated LVE relatives showed that 9 individuals (13%) had development of dilated cardiomyopathy over 10 to 152 months (median, 52). Thirty LVE relatives and 30 age- and sex-matched healthy control subjects were evaluated using 2-dimensional and M-mode echocardiography, tissue Doppler imaging, noninvasive pressure-volume assessment, exercise stress echocardiography, and brain natriuretic peptide levels. LVE relatives showed mild defects of systolic and diastolic LV function, with normal filling pressures and exercise-induced increments in systolic contraction in most cases. LV dimensions and fractional shortening most effectively differentiated LVE relatives from control subjects, with other functional indices lacking additive discriminative value. In a receiver operating characteristics analysis, the area under the curve for LV end-diastolic diameter (% predicted) was 0.96 (P<0.001). LV end-diastolic diameter (% predicted) >116% or LV end-diastolic diameter (% predicted) 112% to 116%+fractional shortening ≤29% had high sensitivity (100%) and specificity (93%) for LVE relatives and identified 8 of 9 progressors. CONCLUSIONS: LVE is a common finding in asymptomatic relatives in dilated cardiomyopathy families and can be a marker of preclinical cardiomyopathy. Assessment of LV size and contractile function is required for differentiating between pathological and physiological causes of LVE and may help to identify those at risk of disease progression.

Negative ionotropic agents for the treatment of left ventricular outflow tract obstruction due to sigmoid septum and concentric left ventricular hypertrophy.

BACKGROUND: Negative ionotropic agents are established treatments for left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM). However, their benefit in those with LVOTO without typical HCM is unclear. We evaluated if negative ionotropic agents are beneficial in treatment of LVOTO in patients without typical HCM. METHOD: In this retrospective cohort study, we evaluated echocardiograms and reviewed records of 15 patients with resting LVOT obstruction due to sigmoid septum (SS, n=9) and mild concentric left ventricular hypertrophy (LVH, n=6). Patients received treatment with sequential negative ionotropic agents (ß-blockers and disopyramide). Initial symptoms, presentation characteristics and echocardiographic characteristics pre and post treatment were evaluated. RESULTS: Fifteen patients (mean age 66.2 years, 46.7% male) were included. Dyspnoea (NYHA Class II/III) was reported as the initial symptom in all patients with four patients reporting chest pain. All patients had hypercontractile LV function at baseline (fractional shortening 46.29±8.77%) but had normal LVS/PW ratio (1.03±0.10). The mean resting LVOT gradient was 74.4±55.2 mmHg. Fourteen patients received initial ß-blocker therapy with a mean reduction in peak LVOT gradient of 40.9 mmHg seen in 11 patients that responded to therapy (p=0.02). Nine patients received disopyramide with a further 24.2±25.8 mmHg reduction in peak LVOT gradient observed in eight patients who tolerated treatment (p=0.04). Symptomatic improvement occurred in 80% of treated patients. CONCLUSIONS: In patients with LVOTO without typical HCM, sequential treatment with negative ionotropes is associated with a significant reduction in the degree of LVOTO and leads to symptomatic improvement.

Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: associations with atrial septal defect and hypoplastic left heart syndrome.

OBJECTIVES: We sought to examine the importance of mutations in the cardiac transcription factor gene NKX2-5 in patients with an atrial septal defect (ASD), patent foramen ovale (PFO), or hypoplastic left heart syndrome (HLHS). BACKGROUND: Mutations in NKX2-5 have been found in families showing secundum ASD and atrioventricular (AV) conduction block and in some individuals with tetralogy of Fallot. The prevalence of NKX2-5 mutations in sporadic cases of ASD/PFO and other forms of congenital heart disease is unknown. METHODS: A cohort of 146 individuals with secundum ASD, PFO complicated by paradoxical embolism, or HLHS were evaluated. Patients with ASD or PFO were ascertained irrespective of family history or associated cardiac abnormalities. The coding region of the NKX2-5 locus was amplified by polymerase chain reaction and sequenced. RESULTS: Among 102 ASD and 25 PFO patients screened, 13 patients (10%) had a positive family history and 5 patients (4%) had AV conduction block. We found one previously documented NKX2-5 missense mutation, T178M, in members of a family with ASD without AV conduction block. One NKX2-5 mutation-positive child from this family had HLHS, although no mutations were subsequently found in 18 patients with sporadic or familial HLHS. In a second ASD family without AV conduction block, we found a missense change, E21Q, previously reported as pathogenic. Because this change did not segregate with disease status, we propose that it is a non-disease-causing polymorphism. CONCLUSIONS: Our findings suggest that NKX2-5 mutations are a relatively infrequent cause of sporadic ASD and HLHS. Screening for NKX2-5 mutations may be warranted in individuals with ASD and a positive family history, irrespective of the presence or absence of AV conduction block.