Alan C. Braverman

The revised Ghent nosology for the Marfan syndrome

The diagnosis of Marfan syndrome (MFS) relies on defined clinical criteria (Ghent nosology), outlined by international expert opinion to facilitate accurate recognition of this genetic aneurysm syndrome and to improve patient management and counselling. These Ghent criteria, comprising a set of major and minor manifestations in different body systems, have proven to work well since with improving molecular techniques, confirmation of the diagnosis is possible in over 95% of patients. However, concerns with the current nosology are that some of the diagnostic criteria have not been sufficiently validated, are not applicable in children or necessitate expensive and specialised investigations. The recognition of variable clinical expression and the recently extended differential diagnosis further confound accurate diagnostic decision making. Moreover, the diagnosis of MFS—whether or not established correctly—can be stigmatising, hamper career aspirations, restrict life insurance opportunities, and cause psychosocial burden. An international expert panel has established a revised Ghent nosology, which puts more weight on the cardiovascular manifestations and in which aortic root aneurysm and ectopia lentis are the cardinal clinical features. In the absence of any family history, the presence of these two manifestations is sufficient for the unequivocal diagnosis of MFS. In absence of either of these two, the presence of a bonafide FBN1 mutation or a combination of systemic manifestations is required. For the latter a new scoring system has been designed. In this revised nosology, FBN1 testing, although not mandatory, has greater weight in the diagnostic assessment. Special considerations are given to the diagnosis of MFS in children and alternative diagnoses in adults. We anticipate that these new guidelines may delay a definitive diagnosis of MFS but will decrease the risk of premature or misdiagnosis and facilitate worldwide discussion of risk and follow-up/management guidelines.

Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2+/− mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1C1039G/+) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β–mediated vasculopathies.

Atenolol versus Losartan in Children and Young Adults With Marfan's Syndrome

BACKGROUND Aortic-root dissection is the leading cause of death in Marfans syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfans syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS Among children and young adults with Marfans syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).

TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome

A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations—a frameshift mutation in exon 6 and a nonsense mutation in exon 4—segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.

Acute Aortic Dissection Clinician Update

A 27-year-old previously healthy woman presented to the emergency room after the sudden onset of severe chest pain and shortness of breath during the 37th week of pregnancy. Her examination was remarkable for a blood pressure of 118/70 mm Hg, heart rate of 100 bpm, and respiratory rate of 24 breaths per minute. The cardiovascular examination was notable for a soft systolic ejection murmur, and the pulmonary and general examinations were unremarkable. ECG demonstrated sinus tachycardia, and her chest x-ray was normal. A D-dimer level was elevated. She underwent a spiral computed tomography scan to evaluate for pulmonary embolism, which instead demonstrated an acute type A aortic dissection and a very small patent ductus arteriosus. The patient underwent emergency cesarean section, which delivered a viable baby, and repair of the type A dissection. Her aortic valve was trileaflet. She had no features on examination to suggest Marfan syndrome or Loeys-Dietz aneurysm syndrome. Her father had died suddenly at 31 years of age of a “presumed heart attack,” and her paternal uncle had undergone ascending aortic aneurysm resection at 42 years of age. Mutation analysis in this woman detected a heterozygous mutation in MYH11 , confirming familial thoracic aortic aneurysm/dissection (TAA/D). Acute aortic dissection is the most common life-threatening disorder affecting the aorta.1 The immediate mortality rate in aortic dissection is as high as 1% per hour over the first several hours, making early diagnosis and treatment critical for survival. Classification schemes for aortic dissection are based on anatomic involvement of the aortic dissection (Figure 1).2 In the DeBakey classification, type I dissections originate in the ascending aorta and extend to at least the aortic arch; type II dissections involve the ascending aorta only; and type III dissections begin in the descending aorta, usually just distal to the …

Transesophageal echocardiographic and clinical features of aortic intramural hematoma

OBJECTIVE This study sought to determine the transesophageal echocardiographic features and natural history of patients with aortic intramural hematoma. METHODS The transesophageal echocardiograms of all patients who had symptoms indicative of aortic dissection over 6 years were reviewed. Measurements were made of the involved aortic segment in the study patients, and follow-up was obtained. RESULTS In patients with aortic intramural hematoma, the wall thickness of the involved segment was significantly greater for descending segments than ascending segments (ascending aorta 7 +/- 2 mm, descending aorta 15 +/- 6 mm, p = 0.0016). In each case, the crescent-shaped intramural hematoma involved one wall predominantly, leading to compression of the aortic lumen. The findings of echolucent areas and displaced intimal calcium were found in the majority of patients. Four of eight patients with intramural hematoma of the ascending aorta were treated medically and four were treated surgically. The 30-day mortality was 50% in the medically treated patients and 0% in the surgically treated group. Four of 11 patients with isolated intramural hematoma of the descending aorta were treated medically and seven were treated surgically. All medically treated and 86% of surgically treated patients were alive at 30 days. CONCLUSIONS Aortic intramural hematoma has distinct and identifiable transesophageal echocardiographic features. These data support those of previous studies documenting high morbidity and mortality in patients with aortic intramural hematoma.

Type-selective benefits of medications in treatment of acute aortic dissection (from the International Registry of Acute Aortic Dissection [IRAD]).

The effects of medications on the outcome of aortic dissection remain poorly understood. We sought to address this by analyzing the International Registry of Acute Aortic Dissection (IRAD) global registry database. A total of 1,301 patients with acute aortic dissection (722 with type A and 579 with type B) with information on their medications at discharge and followed for ≤5 years were analyzed for the effects of the medications on mortality. The initial univariate analysis showed that use of β blockers was associated with improved survival in all patients (p = 0.03), in patients with type A overall (p = 0.02), and in patients with type A who received surgery (p = 0.006). The analysis also showed that use of calcium channel blockers was associated with improved survival in patients with type B overall (p = 0.02) and in patients with type B receiving medical management (p = 0.03). Multivariate models also showed that the use of β blockers was associated with improved survival in those with type A undergoing surgery (odds ratio 0.47, 95% confidence interval 0.25 to 0.90, p = 0.02) and the use of calcium channel blockers was associated with improved survival in patients with type B medically treated patients (odds ratio 0.55, 95% confidence interval 0.35 to 0.88, p = 0.01). In conclusion, the present study showed that use of β blockers was associated with improved outcome in all patients and in type A patients (overall as well as in those managed surgically). In contrast, use of calcium channel blockers was associated with improved survival selectively in those with type B (overall and in those treated medically). The use of angiotensin-converting enzyme inhibitors did not show association with mortality.

Clinical presentation, management, and short-term outcome of patients with type A acute dissection complicated by mesenteric malperfusion: Observations from the International Registry of Acute Aortic Dissection

BACKGROUND Few data exist on clinical/imaging characteristics, management, and outcomes of patients with type A acute dissection and mesenteric malperfusion. METHODS Patients with type A acute dissection enrolled in the International Registry for Acute Dissection (IRAD) were evaluated to assess differences in clinical features, management, and in-hospital outcomes according to the presence/absence of mesenteric malperfusion. A mortality model was used to identify predictors of in-hospital mortality in patients with mesenteric malperfusion. RESULTS Mesenteric malperfusion was detected in 68 (3.7%) of 1809 patients with type A acute dissection. Patients with mesenteric malperfusion were more likely to be older and to have coma, cerebrovascular accident, spinal cord ischemia, acute renal failure, limb ischemia, and any pulse deficit. They were less likely to undergo surgical/hybrid treatment (52.9% vs 87.9%) and more likely to receive only medical (30.9% vs 11.6%) or endovascular (16.2% vs 0.5%) management (P < .001). Overall in-hospital mortality was 63.2% and 23.8% in patients with and without mesenteric malperfusion, respectively (P < .001). In-hospital mortality of patients with mesenteric malperfusion receiving medical, endovascular, and surgical/hybrid therapy was 95.2%, 72.7%, and 41.7%, respectively (P < .001). At multivariate analysis, male gender (odds ratio [OR], 1.7; P = .002), age (OR, 1.1/y; P = .002), and renal failure (OR, 5.9; P = .020) were predictors of mortality whereas surgical/hybrid management (OR, 0.1; P = .005) was associated with better outcome. CONCLUSIONS Type A acute aortic dissection complicated by mesenteric malperfusion is a rare but ominous complication carrying a high risk of hospital mortality. Surgical/hybrid therapy, although associated with 2-fold hospital mortality, appears to be associated with better long-term outcomes in the management of type A acute aortic dissection in this setting.

Acute Aortic Intramural Hematoma: An Analysis From the International Registry of Acute Aortic Dissection

Background— Acute aortic intramural hematoma (IMH) is an important subgroup of aortic dissection, and controversy surrounds appropriate management. Methods and Results— Patients with acute aortic syndromes in the International Registry of Acute Aortic Dissection (1996–2011) were evaluated to examine differences between patients (based on the initial imaging test) with IMH or classic dissection (AD). Of 2830 patients, 178 had IMH (64 type A [42%], 90 type B [58%], and 24 arch). Patients with IMH were older and presented with similar symptoms, such as severe pain. Patients with type A IMH were less likely to present with aortic regurgitation or pulse deficits and were more likely to have periaortic hematoma and pericardial effusion. Although type A IMH and AD were managed medically infrequently, type B IMH were more frequently treated medically. Overall in-hospital mortality was not statistically different for type A IMH compared to AD (26.6% versus 26.5%; P=0.998); type A IMH managed medically had significant mortality (40.0%), although less than classic AD (61.8%; P=0.195). Patients with type B IMH had a hospital mortality that was less but did not differ significantly (4.4% versus 11.1%; P=0.062) from classic AD. One-year mortality was not significantly different between AD and IMH. Conclusions— Acute IMH has similar presentation to classic AD but is more frequently complicated with pericardial effusions and periaortic hematoma. Patients with IMH have a mortality that does not differ statistically from those with classic AD. A small subgroup of type A IMH patients are managed medically and have a significant in-hospital mortality.

Penetrating atherosclerotic ulcers of the aorta.

The term penetrating atherosclerotic aortic ulcer describes a condition in which an atherosclerotic plaque ulcerates and burrows through the internal elastic lamina into the media, leading to a variable amount of intramural hematoma formation. The typical patient is elderly with multiple cardiac risk factors and presents with acute chest or back pain. Diagnosis of penetrating aortic ulcer may be confirmed by computed tomography, magnetic resonance imaging or aortography. Penetrating aortic ulcers usually occur in the mid- and distal descending thoracic aorta and may be complicated by transmural aortic rupture, embolization, pseudoaneurysm formation, or progressive aneurysmal dilatation. The patient with a penetrating ulcer requires close follow-up to detect the development of complications, and may require surgical therapy.