Nupoor Narula

Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2)

Objective To evaluate the prevalence and phenotype of smooth muscle alpha-actin (ACTA2) mutations in non-syndromic thoracic aortic aneurysms and dissections (TAAD). Design Observational study of ACTA2 mutations in TAAD. Setting Centre for Inherited Cardiovascular Diseases. Patients A consecutive series of 100 patients with TAAD. Exclusion criteria included genetically confirmed Marfan syndrome, Loeys–Dietz type 2, familial bicuspid aortic valve and Ehlers–Danlos type IV syndromes. Interventions Multidisciplinary clinical and imaging evaluation, genetic counselling and testing of ACTA2, and family screening. Main outcome measures Prevalence of ACTA2 mutations and corresponding phenotypes. Results TAAD was familial in 43 cases and sporadic in 57 cases. Five mutations in the familial TAAD group (12%) were identified that were absent in controls. The known p.Arg149Cys and the novel p.Asp82Glu, p.Glu243Lys and p.Val45Leu mutations affected evolutionarily conserved residues. The IVS4+1G>A mutation was novel. Of 14 affected relatives, 13 were carriers of the mutation identified in the corresponding proband while one deceased relative had no genetic test. Type A dissection was the first manifestation of aortic aneurysm in four probands and occurred unexpectedly in five relatives. The aortic aneurysm was age dependent and absent in mutated children. Of nine patients who had acute dissection, five died following surgery. At dissection, the size of the aortic aneurysm ranged from 40 mm to 95 mm. Extravascular, ocular, skeletal, nervous and pulmonary traits were variably associated with TAAD, with iris flocculi being most common. Conclusions Timely diagnosis of TAAD in the probands, genetic counselling and family screening identify predisposed relatives and prevent catastrophic aortic dissections.

Autosomal Recessive Atrial Dilated Cardiomyopathy With Standstill Evolution Associated With Mutation of Natriuretic Peptide Precursor A

Background—Atrial dilatation and atrial standstill are etiologically heterogeneous phenotypes with poorly defined nosology. In 1983, we described 8-years follow-up of atrial dilatation with standstill evolution in 8 patients from 3 families. We later identified 5 additional patients with identical phenotypes: 1 member of the largest original family and 4 unrelated to the 3 original families. All families are from the same geographic area in Northeast Italy. Methods and Results—We followed up the 13 patients for up to 37 years, extended the clinical investigation and monitoring to living relatives, and investigated the genetic basis of the disease. The disease was characterized by: (1) clinical onset in adulthood; (2) biatrial dilatation up to giant size; (3) early supraventricular arrhythmias with progressive loss of atrial electric activity to atrial standstill; (4) thromboembolic complications; and (5) stable, normal left ventricular function and New York Heart Association functional class during the long-term course of the disease. By linkage analysis, we mapped a locus at 1p36.22 containing the Natriuretic Peptide Precursor A gene. By sequencing Natriuretic Peptide Precursor A, we identified a homozygous missense mutation (p.Arg150Gln) in all living affected individuals of the 6 families. All patients showed low serum levels of atrial natriuretic peptide. Heterozygous mutation carriers were healthy and demonstrated normal levels of atrial natriuretic peptide. Conclusions—Autosomal recessive atrial dilated cardiomyopathy is a rare disease associated with homozygous mutation of the Natriuretic Peptide Precursor A gene and characterized by extreme atrial dilatation with standstill evolution, thromboembolic risk, preserved left ventricular function, and severely decreased levels of atrial natriuretic peptide.

The need to modify patient selection to improve the benefits of implantable cardioverter-defibrillator for primary prevention of sudden death in non-ischaemic dilated cardiomyopathy

Left ventricular ejection fraction (LVEF) ≤35% is a major determinant for implantable cardioverter-defibrillator (ICD) therapy for primary prevention of sudden death (SD) in patients with non-ischaemic dilated cardiomyopathy (DCM). However, as a risk marker for SD, low LVEF has limited sensibility and specificity. Selecting patients according to the current guidelines shows that most DCM patients do not actually benefit from ICD implantation and may suffer collateral effects and that many patients who are at risk of SD are not identified because a large proportion of SD patients exhibit only mildly depressed LVEF. Identifying patients who are at risk of SD on the sole basis of LVEF appears to be an over-simplification which does not maximize the benefit of ICD therapy. Owing to the complexity of the substrates underlying SD, multiple risk factors used in combination could probably predict the risk of SD better than any individual risk marker. Among non-invasive tests, microvolt T-wave alternans and cardiac magnetic resonance with late gadolinium enhancement may contribute to a better SD risk stratification by their high negative predictive value. Genetics may further contribute because approximately one-third of DCM patients have evidence of familial disease, and mutations in some known disease genes, including LMNA, have been associated with a high risk of SD. In this review, we critically analyse the current indications for ICD implantation and we explore existing knowledge about potentially predicting markers for selecting DCM patients who are at high and low risk of SD.

A novel mutation of the glomulin gene in an Italian family with autosomal dominant cutaneous glomuvenous malformations

Abstract:  Glomuvenous malformations (GVM) are hamartomas characterized histologically by glomus cells, which should be distinguished from glomus tumors. Familial GVM are rare, often present as multiple lesions, and exhibit familial aggregation, with autosomal dominant transmission. GVM are caused by mutations of the glomulin (GLMN) gene on chromosome 1p21‐p22. Their development is thought to follow the ‘two‐hit’ hypothesis, with a somatic mutation required in addition to the inherited germline mutation. We describe a novel GLMN mutation in an Italian family with GVM in which some members present with the less commonly observed phenotype of solitary lesions. A second somatic ‘hit’ mutation in GLMN was not discovered in our family. We further provide histological, immunohistochemical and electron microscopic data exhibiting the classic features of GVM. The diagnosis of GVM is critical because of distinction from venous malformations and blue rubber bleb nevus syndrome, which may demonstrate clinical similarities but require different treatment.

Pathology of plaque haemorrhage and neovascularization of coronary artery.

Intraplaque haemorrhage (IPH) is thought to play crucial roles in plaque progression and plaque rupture, resulting in acute coronary syndromes, which are the leading causes of morbidity and mortality in the developed countries. IPH is a common finding in atherosclerotic plaques. In the past decade, the use of anti-Glycophorin A antibodies that specifically and uniquely label membranes of the red cells triggered a cascade of pathologic and experimental studies concordantly documenting not only the presence but also the major role of IPH in plaque progression and complications. Moreover, recent studies have shown that plaque neovascularization is essential to IPH as a source of blood content. Although the mechanisms by which IPH impacts plaque progression and plaque rupture gradually become clear, several questions such as causes of angioneogenesis, identification and treatment of plaques with angioneogenesis are still unanswered. Further studies are needed to resolve these issues; however, the investigation of IPH without a histopathological approach is unconceivable. This review will focus on the pathology of IPH and plaque neovascularization, pathophysiology and potential clinical impact.

The Pathologic Basis of Recovery

More patients with end-stage heart failure are now being supported by left ventricular assist devices (LVAD) as a bridge to heart transplant. The LVAD unloads the failing heart and modifies the myocardial structure, with regression of left ventricular hypertrophy. The regression of hypertrophy has been reported histomorphologically in paired samples of myocardial tissues obtained from the same patient at the time of LVAD implantation and the heart excised at transplant. The understanding of the mechanisms of recovery may contribute to strategic development for LVAD weaning and the use of LVAD as a destination therapy.

Extra-Aortic Identifiers to Guide Genetic Testing in Familial Thoracic Aortic Aneurysms and Dissections Syndromes: It Is All About the Company One Keeps⁎

Familial thoracic aortic aneurysms and dissections (F-TAADs) are a large group of autosomal dominant, clinically and genetically heterogeneous diseases sharing TAADs as a common phenotype and comprising variable combinations and recurrence of extra-aortic traits ([1–11][1]). Genetic aneurysmal

Cardio-Oncology: The Carney Complex Type I

Cardio-oncology is an important, expanding discipline. Although most developing programs address the cardiotoxicity of old and novel anticancer drugs, cardio-oncology expertise and experience are also needed for rare multiorgan diseases, which require interdisciplinary evaluation to provide optimal

Prevalence of J-Point Elevation in Families With Sudden Arrhythmic Death Syndrome

We congratulate Nunn et al. ([1][1]) for their interesting report published recently in the Journal . They reported that J-point elevation in the inferolateral leads was more prevalent in the first-degree relatives of patients with sudden arrhythmic death syndrome (SADS) than in controls. They