Mutations in TAX1BP3 cause dilated cardiomyopathy with septo-optic dysplasia.

We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo-optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ domain containing protein implicated in regulation of the Wnt/ß-catenin signaling pathway, as the causative mutation. The mutation affects a conserved residue located at the core of TAX1BP3 binding pocket and is predicted to impair the nature of a crucial hydrophobic patch, thereby interrupting the structure and stability of the protein, and its ability to interact with other proteins. TAX1BP3 is highly expressed in heart and brain and consistent with the clinical findings observed in our patients; a knockdown of TAX1BP3 causes elongation defects, enlarged pericard, and enlarged head structures in zebrafish embryos. Thus, we describe a new genetic disorder that expands the monogenic cardiomyopathy disease spectrum and suggests that TAX1BP3 is essential for heart and brain development.

Characterization and long-term outcomes of patients with myocarditis: a retrospective observational study.

INTRODUCTION: There is limited data on the long-term follow-up of patients with myocarditis. AIM: To investigate the long-term follow-up of patients with myocarditis. MATERIAL AND METHODS: We performed a retrospective observational analysis on the clinical long-term outcomes of patients with myocarditis over a 10-year period. The primary outcome was mortality. We identified risk factors for mortality and adverse clinical outcomes. We also compared the characteristics and outcomes of patients presenting with fulminant myocarditis to those presenting with non-fulminant myocarditis. RESULTS: Between May 2004 and December 2014, 203 patients with myocarditis or perimyocarditis were admitted to our center. Most patients were male (87.7%) with a median age at presentation of 33 years (interquartile range: 25.4-38.9). The median follow-up period was 56.9 months (interquartile range 25.3-87.3 months), during which the overall mortality was 4.4% (9 patients). Fifteen patients presented with fulminant myocarditis. After multivariable analysis, older age (HR = 1.11, 95% CI: 1.05-1.16, p < 0.001) and a poorer New York Heart Association (NYHA) function class (HR = 4.6, 95% CI: 1.18-18, p = 0.028) were found to be independently associated with a higher risk of mortality, whereas higher albumin levels at presentation (HR = 0.2, 95% CI: 0.07-0.56, p = 0.002) were associated with decreased mortality. The group presenting with fulminant myocarditis had a more severe course of disease and a higher in-hospital mortality (13.3% vs. 0%, p = 0.005). CONCLUSIONS: The overall prognosis of patients with myocarditis is good - in terms of both survival and recovery without residual left ventricular dysfunction.

Sildenafil in Heart failure (SilHF). An investigator-initiated multinational randomized controlled clinical trial: rationale and design.

AIMS: Heart failure (HF) is a major clinical problem and, despite advances in both pharmacological and device therapy, the mortality remains high and quality of life poor. Over the last decade there has been growing interest in using phosphodiesterase-5 (PDE-5) inhibitors in HF associated with group 2 pulmonary hypertension (PH), with benefits reported on pulmonary haemodynamic and functional status in single-centre trials Methods The Sildenafil in Heart Failure (SilHF) trial is a randomized, placebo-controlled multinational trial designed to assess efficacy and tolerability of PDE-5 inhibition with sildenafil (target dose 40 mg three times per day) in 210 patients with HF, New York Heart Association (NYHA) functional class II or III, and evidence of group 2 PH. The co-primary endpoints are patient global assessment and the 6 min walk test. Secondary endpoints include NYHA functional class and the quality of life tools Euro QoL 5D and the Kansas City questionnaire. Patients will be followed up for 6 months. PERSPECTIVE: The authors hypothesize that PDE-5 inhibition can improve exercise capacity and symptoms with acceptable tolerability in patients with HF and group 2 PH.

Tissue Doppler imaging in patients with advanced heart failure: relation to functional class and prognosis.

BACKGROUND: Tissue Doppler imaging (TDI) provides rapid assessment of systolic and diastolic myocardial function. However, the added value of TDI to standard Doppler echocardiographic measurements in predicting symptoms and outcome of advanced heart failure remains unknown. METHODS: The study cohort comprised 45 patients with congestive heart failure, defined as New York Heart Association functional class III and IV, who were referred to our department for evaluation for heart transplantation. Twenty healthy subjects were the controls. Conventional echo Doppler was used to assess left ventricular (LV) ejection fraction, peak velocities of transmitral early and late diastolic LV filling, the ratio of transmitral early to late LV filling velocity, and E-deceleration time. TDI measurements recorded at the mitral annulus included systolic velocity, early and late diastolic velocities, and the ratio of early to late diastolic velocity. The ratio of transmitral early LV filling velocity to early diastolic TDI velocity of the mitral annulus (E/E') was calculated. All patients were followed for cardiac-related death and hospitalization for heart failure. RESULTS: Patients with functional class IV had a significantly higher E/E' ratio than did patients with functional class III (12.9 +/- 2.8 vs 8.3 +/- 1.7, p < 0.001) and the controls (5.4 +/- 1.3, p < 0.001). Except for transmitral late filling velocity, all conventional echo Doppler parameters and TDI variables significantly correlated with functional class. On multivariate stepwise analysis, however, the E/E' ratio was the only independent predictor of functional class (p = 0.003). E/E' also correlated with cardiac mortality and hospitalization. CONCLUSION: Conventional Doppler indices and TDI parameters correlated with functional class in patients with advanced heart failure. The E/E' ratio, which probably reflects high LV end-diastolic pressure, was the best measure for differentiating patients with functional class III and IV, and it also correlated with cardiac mortality and hospitalization for worsening heart failure, thereby providing additional value to standard echocardiographic measures.