Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-ß signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-ß signaling.Genet Med 19 4, 386-395.

Brachial artery occlusion in a young adult with an ACTA2 thoracic aortic aneurysm.

Mutations of the ACTA2 gene, which encodes the smooth muscle cell-specific isoform of α-actin protein, have recently been found to be among the most common genetic abnormalities observed in patients with familial thoracic aortic aneurysms/dissection (TAAD). Other reported vascular manifestations caused by these mutations include premature coronary artery disease and stroke. We report a young adult who presented with an acute brachial artery occlusion and was subsequently found to have aortopathy and an ACTA2 mutation. This expands the spectrum of vascular disease associated with ACTA2 mutation to include acute limb ischemia.

Cardiovascular outcomes of pregnancy in Turner syndrome.

OBJECTIVES: Women with Turner syndrome (TS) are frequently counselled against pregnancy due to lack of data and unclear aortic dissection risk. However, with advances in fertility therapy, more women with TS are contemplating pregnancy. This study compared rates of adverse cardiovascular (CV) outcomes among: (1) pregnant and non-pregnant women with TS and (2) pregnant women with TS with/without structural heart disease. METHODS: Retrospective analysis of pregnant and age-matched non-pregnant controls with TS (2005-2017) across 10 CV centres was done. Data were collected at initial evaluation in pregnancy and outcomes were assessed to 6 months postpartum. Adverse CV events were defined as CV death, aortic dissection/rupture and/or aortic intervention. Non-pregnant age-matched controls were followed over the same time period. RESULTS: Sixty-eight pregnancies were included (60 women, mean age 33 years, 48% primigravid, 49% fertility therapy, 80% structurally normal heart, 25% XO karyotype). Based on American Society of Reproductive Medicine criteria, 10 pregnancies occurred in women stratified to high-risk category. There were no CV events in the pregnant women or in the non-pregnant women with TS. Obstetric events complicated 12 (18%) pregnancies with 9 (13%) attributed to hypertensive disorder of pregnancy. Fetal events included small for gestational age neonates (18%), preterm delivery (15%) and fetal death (3%). CONCLUSIONS: This study helps to refine the approach to pregnancy in women with TS. Among women with TS without structural heart disease, pregnancy does not impose an increased risk of CV outcomes. Among women with TS with structural heart disease, the risk of pregnancy is not as prohibitive as previously described but does require ongoing evaluation.

Risk prediction models for heart failure admissions in adults with congenital heart disease.

BACKGROUND: Heart failure (HF) is the leading cause of death in adult patients with congenital heart disease (ACHD). No risk prediction model exists for HF hospitalization (HFH) for ACHD patients. We aimed to develop a clinically relevant one-year risk prediction system to identify ACHD patients at high risk for HFH. METHODS: Data source was the Quebec CHD Database. A retrospective cohort including all ACHD patients aged 18-64 (1995-2010) was constructed for assessing the cumulative risk of HFH adjusting for competing risk of death. To identify one-year predictors of incident HFH, multivariable logistic regressions were employed to a nested case-control sample of all ACHD patients aged 18-64 in 2009. The final model was used to create a risk score system based on adjusted odds ratios. RESULTS: The cohort included 29,991 ACHD patients followed for 648,457 person-years. The cumulative HFH risk by age 65 was 12.58%. The case-control sample comprised 26,420 subjects, of whom 189 had HFHs. Significant one-year predictors were age ≥ 50, male sex, CHD lesion severity, recent 12-month HFH history, pulmonary arterial hypertension, chronic kidney disease, coronary artery disease, systemic arterial hypertension, and diabetes mellitus. The created risk score ranged from 0 to 19. The corresponding HFH risk rose rapidly beyond a score of 8. The risk scoring system demonstrated excellent prediction performance. CONCLUSIONS: One eighth of ACHD population experienced HFH before age 65. Age, sex, CHD lesion severity, recent 12-month HFH history, and comorbidities constructed a risk prediction model that successfully identified patients at high risk for HFH.

Mobile ventricular thrombus arising from the mitral annulus in patients with dense mitral annular calcification.

Mitral annular calcification (MAC) has been considered a risk factor for thrombo-embolic disease. Superimposed thrombus formation on MAC has not been well described as a possible underlying mechanism for this association. We report three patients with mobile left ventricular (LV) thrombus arising from the LV aspect of severe calcified mitral annulus in the setting of normal LV function, mitral valve function, and sinus rhythm.

Non-Vitamin K Antagonist Oral Anticoagulants in Adult Congenital Heart Disease.

Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have several advantages over VKAs that render them an attractive option for adults with congenital heart disease (CHD). Efficacy and safety data specific to the adult CHD population are emerging. Herein, we synthesize the growing literature regarding NOACs in adults with CHD and attempt to identify subgroups for which it appears reasonable to extrapolate data from populations without CHD. Small observational studies suggest that NOACs are safe and effective in selected adults with CHD. NOACs are contraindicated in patients with a mechanical valve, in those with mitral or tricuspid valve stenosis with enlarged and diseased atria, with or without a mitral or tricuspid bioprosthesis, and after recent cardiac surgery (< 3 months). There is currently insufficient evidence to recommend NOACs in patients with a Fontan circulation or cyanotic CHD. Growing literature supports the use of NOACs in patients without CHD who have various forms of valvular heart disease. Therefore, when an indication for oral anticoagulation is established, it appears reasonable to consider a NOAC instead of a VKA in adults with CHD lesions analogous to isolated mitral regurgitation, tricuspid regurgitation, or aortic regurgitation or stenosis. The NOAC agent selected and the prescribed dose should be tailored according to bleeding risk, body weight, renal function, and comedications, especially antiepileptic drugs. The decision to initiate a NOAC should be shared between the patient and care provider. Large-scale research studies are required to further assess safety and efficacy in selected patient subgroups.

Consensus recommendations for echocardiography in adults with congenital heart defects from the International Society of Adult Congenital Heart Disease (ISACHD).

The population of adults with congenital heart disease (ACHD) is increasing constantly due to medical, surgical and interventional successes and the input from advanced cardiovascular imaging. ACHD patients are at continuing risk of residua and sequelae related to their CHD contributing to significant morbidity and mortality. Consequently, lifelong expert surveillance is recommended for most patients. Healthcare providers are still working out how best to achieve this objective, how to train enough experts to provide high quality care, and how to organize the delivery of care. Echocardiography is crucial to clinical surveillance providing a comprehensive assessment of cardiac morphology, physiology, pathophysiology, and function. Thus it contributes significantly to the overall clinical management of ACHD patients. The International Society for Adult Congenital Heart Disease (ISACHD; www.isachd.org) is the leading organization of professionals worldwide dedicated to the pursuit of excellence in the care of ACHD patients. Recognizing the critical role of imaging in the diagnosis and management of ACHD, ISACHD established a task force to provide guidance on echocardiographic studies and reporting. The rationale is that standardization of echocardiographic imaging and reporting carries the potential to improve the overall quality of these exams around the world and facilitate collaborative multicenter research. The standardized ACHD protocols provided by the ISACHD task force (found in the appendices) include specific recommendations for data acquisition and reporting for each of the major adult congenital heart lesions. These protocols give a comprehensive and structured approach in the evaluation of ACHD patients and help to ensure excellent patient care.

Acute reversible left ventricular dysfunction secondary to alcohol.

Chronic excess alcohol use is a well-established cause of dilated cardiomyopathy. The clinical features are variable because patients may be asymptomatic despite there being evidence of severe left ventricular dysfunction. Although the mechanism of alcohol-induced cardiomyopathy is not clearly understood, abstinence from alcohol has been associated with improvement in left ventricular function. Conversely, patients with ongoing alcohol abuse and dilated cardiomyopathy have a poor prognosis, with progressive biventricular failure and, ultimately, death. A case of rapid reversal of alcohol-induced cardiomyopathy with abstinence is reviewed. The present case highlights the acute toxic nature of alcohol and the potential for rapid functional recovery.

Prevalence and clinical manifestations of 22q11.2 microdeletion in adults with selected conotruncal anomalies.

OBJECTIVES: This study was designed to determine the prevalence and clinical manifestations of 22q11.2 microdeletion in adults with selected conotruncal anomalies and to assess the clinician's ability to predict the presence or absence of 22q11.2 microdeletion on the basis of clinical features. BACKGROUND: It is known that 22q11.2 microdeletion is a chromosomal anomaly with cardiac and extracardiac manifestations. The prevalence and manifestations in adults have not been well characterized. METHODS: A total of 103 consecutive adults with either tetralogy of Fallot (TOF), pulmonary atresia/ventricular septal defect (PA/VSD), or truncus arteriosus (TA) were prospectively screened for 22q11.2 microdeletion using a fluorescence in situ hybridization (FISH) assay. Clinicians were asked to predict 22q11.2 microdeletion status on the basis of clinical features. A geneticist blinded to FISH assay results reviewed photographs of the patients for typical dysmorphic features of 22q11.2 microdeletion. RESULTS: Six patients (prevalence 5.8%, 95% confidence interval 1.3 to 10.3) had 22q11.2 microdeletion (3 with TOF, 2 with PA/VSD, 1 with TA). In two of these patients, the clinician incorrectly predicted absence of the deletion. In three, typical dysmorphic features of 22q11.2 microdeletion were absent. CONCLUSIONS: Our work showed that 22q11.2 microdeletion is under-recognized in adults with congenital heart disease. The absence of typical phenotypic features makes it difficult to correctly predict if the deletion is present. Screening for 22q11.2 microdeletion should be considered in adults with high-risk cardiac lesions, as it has important implications in reproductive counseling and surveillance for associated extracardiac manifestations.

Ruptured mycotic pseudoaneurysm of the thoracic aorta.

A 68-year-old man being treated for a Staphylococcus aureus bacteremia developed hemoptysis. A transesophageal echocardiogram (TEE) and computed tomographic (CT) scan showed a large descending thoracic aorta pseudoaneurysm. The patient died before surgical intervention could be performed. Pathological examination revealed the presence of a saccular pseudoaneurysm originating from a mural defect at the site of an ulcerated atherosclerotic plaque. There was rupture into the mediastinum with contained hematoma. Microscopic examination documented numerous Gram-positive bacterial cocci at the rupture site.

Pulmonary hypertension and patent ductus arteriosus in an 82-year-old female patient.

An 82-year-old female patient with a history of deep vein thrombosis presented with progressive dyspnea. Echocardiogram demonstrated significant pulmonary hypertension and patent ductus arteriosus (PDA). There was considerable debate regarding the role of PDA in the patient's pulmonary hypertension. The patient died of heart failure a few months later. Autopsy demonstrated extensive chronic pulmonary thromboembolic disease. Pulmonary thromboemboli continue to be a diagnostic challenge despite modern diagnostic modalities. Autopsy continues to play a role in investigating unexplained clinical findings and in determining cause of death.

Outcome of the unoperated adult who presents with congenitally corrected transposition of the great arteries.

OBJECTIVES: The goal of this study was to determine the presentation and outcome of the unoperated adult with congenitally corrected transposition of the great arteries. BACKGROUND: The presentation of this disorder and the outcome in unoperated adults have not been well defined. METHODS: All unoperated patients > or =18 years old were evaluated for spectrum of disease, hemodynamic severity, timeliness of diagnosis and referral, and outcome. RESULTS: Forty-four patients aged 20 to 79 years (mean, 44) were followed up to 144 months. In 29 (66%), the correct diagnosis was first made at age > or =18 years; the diagnosis was missed in seven of these patients in a prior cardiology consultation, despite cardiac imaging. Systemic atrioventricular valve (SAVV) regurgitation (grade > or =3/4) was noted in 26 patients (59%). Thirty (68%) had surgical intervention, including SAVV replacement in all, with no early mortality. Preoperatively, this subset had significant dysfunction of the systemic ventricle (SV) (ejection fraction [EF], 40 +/- 10%), and most had advanced symptoms (25 with ability index > or =2/4). In 16 (53%), SAVV regurgitation > or =3/4 and ventricular dysfunction had been documented for >6 months. The mean EF of the SV decreased significantly postoperatively (34 +/- 11%, p = 0.006). Four patients (13%) eventually required cardiac transplantation. Poor preoperative EF of the SV predicted eventual need for transplantation (p = 0.001). CONCLUSIONS: Patients with unoperated congenitally corrected transposition of the great arteries are often misdiagnosed in adulthood and are referred late despite symptomatic SAVV regurgitation and significant SV dysfunction. Although excellent early surgical results can be achieved, significant residual dysfunction of the SV is common.

Cardiogenic shock in Takotsubo cardiomyopathy: a focus on management.

Takotsubo cardiomyopathy has become a well recognized mimicker of acute coronary syndrome. Patients generally do well, although a minority can develop life-threatening complications. We present a case of 1 such patient in a branched self-assessment format designed to challenge the reader's clinical management skills.

Severe aortic insufficiency secondary to an aortic bioprosthesis tear.

A patient with a 10-year-old Medtronic Hancock II porcine aortic bioprosthesis developed severe aortic insufficiency. A transesophageal echocardiogram showed a long and mobile mass attached to the bioprosthesis which was consistent with a torn cusp. The patient underwent replacement of the prosthesis with a mechanical valve. Pathological examination showed two subacute tears arising from the same suture buttressing site. These two tears allowed a portion of the valve apparatus to prolapse.

Temporal variations in effective orifice area during ejection in patients with valvular aortic stenosis.

Effective orifice area (EOA) is the standard index for assessing aortic stenosis (AS) severity. However, EOA varies during ejection and a single measurement at 1 ejection time point may not fully describe the hemodynamic severity of a stenotic aortic valve. We investigated whether the dynamic change in EOA during ejection differs between patients with severe AS (EOA /=80% of maximum EOA for a shorter duration during ejection compared with control patients (49 +/- 25 vs 64 +/- 14%, P =.05). EOA opening rate, time to maximum V(LVOT), time to maximum V(AS), and time to 80% of maximum EOA correlated with mean pressure gradient (r = -0.80, 0.63, 0.42, and 0.54, respectively, n = 45). Indices of ejection dynamics and valve kinetics differ in patients with AS and may provide further insight into the hemodynamic or physiologic severity of a stenotic aortic valve.

Acute aortic intimal tear without a mobile flap mimicking an intramural hematoma.

Several variants of aortic pathology must be considered in the differential diagnosis of the patient presenting with an acute aortic syndrome. In addition to aortic dissection, such entities include intramural hematoma, penetrating aortic ulcer, and localized intimal tear without dissection. These lesions, which lack a mobile intimal flap, may be difficult to correctly identify by transesophageal echocardiography or other imaging modalities. We present a case of an acute aortic syndrome with unusual features on transesophageal echocardiography.