Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Role of the phosphoinositide signalling system in the genesis of cardiac hypertrophy.

The genesis of left ventricular hypertrophy in hypertension is usually regarded as a physiological response to increased haemodynamic load. However, there is growing evidence that the presence of cardiac hypertrophy is an independent and important risk factor for cardiovascular morbidity and mortality. Therefore, it is of fundamental importance to delineate the mechanisms by which cardiac growth occurs but at present these processes are ill understood. In certain cells control of growth is thought to involve the hydrolysis of inositol lipids and the induction of protooncogenes. Moreover, several of the stimuli which may initiate cardiomyocyte growth, such as myocardial wall stretch, a1 and angiotensin II receptor agonists, also stimulate cardiac phosphoinositide turnover. This thesis considers the hypothesis that phosphoinositide metabolism is increased in the left ventricle during the development of cardiac hypertrophy. Three related proto-oncogenes were also studied: rasH, which may encode the G protein (Gp) and the nuclear proto-oncogenes c-myc and c-fos which are induced following activation of this pathway. Two models of hypertension were studied; a genetic form called the spontaneously hypertensive rat (SHR) and coarctation hypertension using a ligature placed on the abdominal aorta. Significant hypertension was induced following coarctation of the aorta compared with sham operated animals both at 3 and 9 days. There was cardiac hypertrophy demonstrable at 3 and 9 days which progressed further by 28 days. Following a 2 hour incubation with [3H] inositol, labelled Ins1,4,5P3 and InsP2 were increased in the left ventricle of the coarctation group at 3 days. By 9 days these differences were no longer sustained. Moreover, total Ins1,4,5P3 was increased at 3 days in the hypertensive group compared with sham operated animals but were not significantly different at 9 days. At 3 days levels of rasH, c-myc and c-fos had increased in animals with coarctation. However, by 9 days the levels of rasH and c-myc decreased in the hypertensive group compared with control animals. No difference was observed in c-fos between the two groups. Spontaneously hypertensive rats were hypertensive by 5 weeks of age compared to the normotensive control group (Wistar Kyoto, WKY) and the blood pressure increased further by 12 weeks. Cardiac hypertrophy was observed at 5 and 12 weeks. Accumulation of [3H] inositol monophosphate within the left ventricle in the presence of lithium was not different at either 5 or 12 weeks of age. There was no significant difference in labelling of Ins1,4,5P3 at 5 weeks or total Ins1,4,5P3 at 5 and 12 weeks of age. There was a significantly lower level of rasH at both 5 weeks and at 12 weeks of age in the SHR compared with WKY. No differences were observed in c- myc or c-fos levels in either strain at these ages. It is concluded that myocardial phosphoinositide metabolism and levels of certain related proto-oncogenes were increased during the early stages of the development of cardiac hypertrophy in coarctation hypertension. Such processes may be involved in the initial phase of the genesis of cardiac hypertrophy in this model

The Key Roles of Negative Pressure Breathing and Exercise in the Development of Interstitial Pulmonary Edema in Professional Male SCUBA Divers

Abstract Background Immersion pulmonary edema is potentially a catastrophic condition; however, the pathophysiological mechanisms are ill-defined. This study assessed the individual and combined effects of exertion and negative pressure breathing on the cardiovascular system during the development of pulmonary edema in SCUBA divers. Methods Sixteen male professional SCUBA divers performed four SCUBA dives in a freshwater pool at 1 m depth while breathing air at either a positive or negative pressure both at rest or with exercise. Echocardiography and lung ultrasound were used to assess the cardiovascular changes and lung comet score (a measure of interstitial pulmonary edema). Results The ultrasound lung comet score was 0 following both the dives at rest regardless of breathing pressure. Following exercise, the mean comet score rose to 4.2 with positive pressure breathing and increased to 15.1 with negative pressure breathing. The development of interstitial pulmonary edema was significantly related to inferior vena cava diameter, right atrial area, tricuspid annular plane systolic excursion, right ventricular fractional area change, and pulmonary artery pressure. Exercise combined with negative pressure breathing induced the greatest changes in these cardiovascular indices and lung comet score. Conclusions A diver using negative pressure breathing while exercising is at greatest risk of developing interstitial pulmonary edema. The development of immersion pulmonary edema is closely related to hemodynamic changes in the right but not the left ventricle. Our findings have important implications for divers and understanding the mechanisms of pulmonary edema in other clinical settings

Vorapaxar in the secondary prevention of atherothrombotic events

Item does not contain fulltextBACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)