ARHGAP18 Protects Against Thoracic Aortic Aneurysm Formation by Mitigating the Synthetic and Proinflammatory Smooth Muscle Cell Phenotype.

RATIONALE: Thoracic aortic aneurysm (TAA) is a potentially lethal condition, which can affect individuals of all ages. TAA may be complicated by the sudden onset of life-threatening dissection or rupture. The underlying mechanisms leading to TAA formation, particularly in the nonsyndromal idiopathic group of patients, are not well understood. Thus, identification of new genes and targets that are involved in TAA pathogenesis are required to help prevent and reverse the disease phenotype. OBJECTIVE: Here we explore the role of ARHGAP18, a novel Rho GAP expressed by smooth muscle cells (SMCs), in the pathogenesis of TAA. METHODS AND RESULTS: Using human and mouse aortic samples, we report that ARHGAP18 levels were significantly reduced in the SMC layer of aortic aneurysms. Arhgap18 global knockout (Arhgap18-/-) mice exhibited a highly synthetic, proteolytic, and proinflammatory smooth muscle phenotype under basal conditions and when challenged with angiotensin II, developed TAA with increased frequency and severity compared with littermate controls. Chromatin immunoprecipitation studies revealed this phenotype is partly associated with strong enrichment of H3K4me3 and depletion of H3K27me3 at the MMP2 and TNF-α promoters in Arhgap18-deficient SMC. We further show that TAA formation in the Arhgap18-/- mice is associated with loss of Akt activation. The abnormal SMC phenotype observed in the Arhgap18-/- mice can be partially rescued by pharmacological treatment with the mTORC1 inhibitor rapamycin, which reduces the synthetic and proinflammatory phenotype of Arhgap18-deficient SMC. CONCLUSION: We have identified ARHGAP18 as a novel protective gene against TAA formation and define an additional target for the future development of treatments to limit TAA pathogenesis.

Rare non-synonymous variations in the transcriptional activation domains of GATA5 in bicuspid aortic valve disease.

Bicuspid aortic valve (BAV) is the commonest congenital heart disease and a highly heritable trait; however, only the NOTCH1 gene has been linked to limited cases of BAV in humans. Recently, the transcription factor GATA5 has been shown to have an essential role in aortic valve development, and targeted deletion of Gata5 in mice is associated with partially penetrant BAV formation. Here, we investigated the relationship between GATA5 gene variants and BAV with its associated aortopathy. One hundred unrelated individuals with confirmed BAV were prospectively recruited. Following collection of clinical information and DNA extraction, the coding regions and splice signal sequences of the GATA5 gene were screened for sequence variations. The clinical characteristics of the cohort included a male predominance (77%), mean age of diagnosis 29 ± 22 years, associated aortopathy in 59% and positive family history for BAV in 13%. Genetic analysis identified the presence of 4 rare non-synonymous variations within the GATA5 transcriptional activation domains, namely Gln3Arg, Ser19Trp, Tyr142His and Gly166Ser, occurring in one patient each. Gln3Arg and Tyr142His substitutions affect highly conserved and functionally relevant residues, and are likely to impact on the transcriptional activation of GATA5 target regions. A novel Ser19Trp variation was identified at a highly conserved amino acid residue in one patient, while the Gly166Ser variant was found in a familial case of BAV and associated aortopathy. Rare non-synonymous variations in the functionally important GATA5 transcriptional activation domains may be important in the pathogenesis of BAV disease in humans.

Development and validation of a time-dependent risk model for predicting mortality in infective endocarditis.

AIMS: Existing risk models in infective endocarditis (IE) have not investigated whether the prognostic value of clinical parameters is time-dependent. We have explored the potential of time-dependent risk stratification to predict outcome in IE. METHODS AND RESULTS: We studied 273 patients admitted with IE to two centres (derivation cohort n=192, validation cohort n=81). The derivation cohort was used to identify independent predictors of 6 months mortality at days 1, 8, and 15 (multivariable Cox regression, P<0.05). There were six predictors at day 1, five at day 8, and only three at day 15. Whereas heart failure, thrombocytopenia, and severe comorbidity predicted mortality at all three time-points, other predictors were time-dependent (age, tachycardia, renal impairment at day 1; severe embolic events, renal impairment at day 8). These predictors were incorporated into a time-dependent model. The model was validated in an independent cohort with concordance indices of 0.79 (95% CI 0.68-0.91) at day 1, 0.79 (95% CI 0.65-0.93) at day 8, and 0.84 (95% CI 0.73-0.95) at day 15. Six months mortality was 2.4% in patients deemed as low-risk at all time-points, compared with 78.2% in patients classified as high-risk at any evaluation. CONCLUSION: Prognostic factors in IE are time-dependent. Time-dependent risk stratification accurately predicts outcome in IE.

Long-term follow-up of patients with obstructive hypertrophic cardiomyopathy treated with dual-chamber pacing.

In this study, patients with obstructive hypertrophic cardiomyopathy (HC) were treated with dual-chamber pacemaker therapy. Long-term follow-up analysis showed that dual-chamber pacemaker therapy in selected patients resulted in a significant reduction in symptoms and in the left ventricular outflow tract gradient, which was maintained up to 10 years after implantation. Dual-chamber pacing is of potential long-term benefit in selected groups of patients with obstructive HC.

Surgery for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetically determined cardiac disease characterised by otherwise unexplained myocardial hypertrophy of the left ventricle, and may result in left ventricular outflow tract obstruction. It is the most common cause of sudden cardiac death in young adults due to arrhythmias. Septal myectomy is a surgical treatment for HCM with moderate to severe outflow tract obstruction, and is indicated for patients with severe symptoms refractory to medical therapy. The surgical approach involves obtaining access to the interventricular septum via transaortic, transapical or transmitral approaches, and excising a portion of the hypertrophied myocardium to relieve the outflow tract obstruction. Large, contemporary series from centres experienced in septal myectomy patients have demonstrated a low early mortality of <2 %, excellent long-term survival that matches the general population, and durable relief of symptoms.

Long-term follow-up of implantable cardioverter defibrillator therapy for hypertrophic cardiomyopathy.

In this study, high-risk patients with hypertrophic cardiomyopathy were treated with an implantable defibrillator. Long-term follow-up analysis showed the efficacy of implantable defibrillator therapy, with patients having an appropriate device intervention at a rate of 11%/year, thereby preventing sudden death in an Australian population.

Sudden death prevented in hypertrophic cardiomyopathy.

The most common cause of sudden cardiac death in individuals aged less than 35 years, including competitive athletes, is the inherited disorder hypertrophic cardiomyopathy (HCM). Until recently, no therapeutic intervention had been identified to prevent sudden death in HCM. This case report highlights the role of the implantable cardioverter defibrillator (ICD) in preventing sudden death in patients with HCM. The report highlights the importance of risk stratification in patients with HCM in order to identify those individuals who would most likely benefit from ICD therapy. The ICD implantation is now the treatment of choice in preventing sudden death in selected (highest risk) populations with HCM. In the future, understanding the molecular basis of sudden death in HCM may identify potential new gene-based therapeutic strategies.