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Diseases of the thoracic aorta include inflammatory, degenerative and inherited conditions, which can result in aneurysm formation and also dissection or rupture of the aorta. The progression of aortic disease can be clinically silent, and external physical features may be absent or subtle.

Background Abnormal flow dynamics play an early and causative role in pathologic changes of the ascending aorta. Purpose To identify: 1) the changes in flow, shape, and size that occur in the ascending aorta with normal human ageing and 2) the influence of these factors on aortic flow dynamics. Study type Retrospective. Subjects In all, 247 subjects (age range 19-86 years, mean 49 ± 17.7, 169 males) free of aortic or aortic valve pathology were included in this study. Subjects were stratified by youngest (18-33 years; n = 64), highest (>60 years, n = 67), and the middle two quartiles (34-60 years, n = 116). Field strength/sequence Subjects underwent a cardiac MRI (3T) exam including 4D-flow MRI of the aorta. Assessment Aortic curvature, arch shape, ascending aortic angle, ascending aortic diameter, and the stroke volume normalized by the aortic volume (nSV) were measured. Velocity, vorticity, and helicity were quantified across the thoracic aorta. Statistical tests Univariate and multivariate regressions were used to quantify continuous relationships between variables. Results Aortic diameter, ascending aortic angle, shape, and curvature all increased across age while nSV decreased (all P 10 times that of diameter and other shape factors. Data conclusion Aortic shape influences flow dynamics in younger subjects. Flow conditions become increasingly disturbed with advancing age, and in these conditions nSV has a more dominant effect on flow patterns than shape factors. Level of evidence 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:90-100.

Marfan syndrome is consequent upon mutations in FBN1, which encodes the extracellular matrix microfibrillar protein fibrillin-1. The phenotype is characterised by development of thoracic aortic aneurysm. Current understanding of the pathogenesis of aneurysms in Marfan syndrome focuses upon abnormal vascular smooth muscle cell signalling through the transforming growth factor beta (TGFβ) pathway. Angiotensin II (Ang II) can directly induce aortic dilatation and also influence TGFβ synthesis and signalling. It has been hypothesised that antagonism of Ang II signalling may protect against aortic dilatation in Marfan syndrome. Experimental studies have been supportive of this hypothesis, however results from multiple clinical trials are conflicting. This paper examines current knowledge about the interactions of Ang II and TGFβ signalling in the vasculature, and critically interprets the experimental and clinical findings against these signalling interactions. Keywords: Aneurysm, Angiotensin blocker, Cell Signalling, Clinical trial

Background: Bicuspid aortic valve (BAV) is a common congenital heart disease which is associated with aortic dilatation. There is controversy in the literature regarding the various measures of the biomechanical properties of the aorta in these patients and their relationship to aortic dilatation. The present study aimed to assess both conventional 2D Cardiac Magnetic Resonance Imaging (CMRI) measurements of aortic biomechanics (compliance and distensibility) and a computational fluid dynamics (CFD) approach in patients with BAV and either normal or dilated ascending aorta. Methods: 2D CMRI was performed in 18 patients (6 controls, 6 BAV with dilated ascending aorta and 6 BAV with normal ascending aorta i.e.

Background Non-syndromal thoracic aortic aneurysm and dissection (ns-TAAD) is a genetic aortopathy, with uncertain incidence. This study documented the incidence of ns-TAAD and outcomes of family screening over 15years. Methods Consecutive series of 2385 patients with aortic disease in prospective registry (2000 to 2014), including 675 undergoing surgery. Diagnosis of ns-TAAD included family history, aortic imaging, tissue pathology and mutation testing. Screening was offered to relatives of ns-TAAD probands, with follow-up for affected individuals. Results There were 270 ns-TAAD probands (74% males), including 116 (43%) presenting with aortic dissection. Among surgical cases, a diagnosis of ns-TAAD was established for 116 (17%). Age of probands was 50.4±14.1years, with aortic diameter of 51±12mm. Screening of 581 at-risk relatives identified 216 new ns-TAAD cases (detection rate=37%). Among 71 probands with known family history, screening identified 130 new affected relatives and among 53 probands with no family history, screening identified 86 new affected relatives. Mean age of new affected relatives at diagnosis was 44±18years, with aortic diameter of 42±7mm, including 42 with diameter>50mm. Ten-year mortality was similar for probands without dissection (7.7±3.1%) and new affected relatives (11.4±4.0%) but greater for probands surviving initial dissection (27.6±7.8%, p=0.003). Conclusions Up to 1 in 6 patients undergoing aortic surgery have features of ns-TAAD, frequently presenting as aortic dissection but at later age than other genetic aortopathies. Family screening identifies affected relatives in up to half of ns-TAAD probands, many of whom already have significant aortic dilatation.

Background Genetic aortopathy (GA) underlies thoracic aortic aneurysms (TAA) in younger adults. Comparative survival and predictors of outcomes in nonsyndromic TAA (NS-TAA) are incompletely defined compared to Marfan syndrome (MFS) and bicuspid aortic valve (BAV). Objectives The study sought to compare survival and clinical outcomes for individuals with NS-TAA, MFS, and BAV. Methods From 1988 to 2014, all patients presenting with GA 16 to 60 years of age were enrolled in a prospective study of clinical outcomes. Risk factors for death and aortic dissection were identified by Cox proportional hazards modeling and a mortality risk score developed. Results Diagnosis of GA was made for 760 patients (age 36.9 ± 13.6 years, 26.8% female; NS-TAA, n = 311; MFS, n = 221; BAV, n = 228). MFS patients were younger than NS-TAA and BAV. Presentation with aortic dissection was more common for NS-TAA than MFS or BAV. The 687 patients surviving >30 days after presentation were followed for a median of 7 years. Calculated 10-year mortality was 7.8% for NS-TAA, 8.7% for MFS, and 3.5% for BAV (NS-TAA and MFS vs. BAV p Conclusions Clinical outcomes for MFS and NS-TAA are similar but worse than BAV. Independent predictors of mortality, including family history of aortic dissection and age, can be included in an Aortopathy Mortality Risk Score to predict survival. Management of NS-TAA, including surgical intervention, should be similar to that of MFS.

Background The Freestyle stentless bioprosthesis (FSB) has been demonstrated to be a durable prosthesis in the aortic position. We present data following Freestyle implantation for up to 10 years post-operatively and compare this with previously published results. Methods A retrospective cohort analysis of 237 patients following FSB implantation occurred at five Australian hospitals. Follow-up data included clinical and echocardiographic outcomes. Results The cohort was 81.4% male with age 63.2±13.0 years and was followed for a mean of 2.4±2.3 years (range 0-10.9 years, total 569 patient-years). The FSB was implanted as a full aortic root replacement in 87.8% patients. The 30-day all cause mortality was 4.2% (2.0% for elective surgery). Cumulative survival at one, five and 10 years was 91.7±1.9%, 82.8±3.8% and 56.5±10.5%, respectively. Freedom from re-intervention at one, five and 10 years was 99.5±0.5%, 91.6±3.7% and 72.3±10.5%, respectively. At latest echocardiographic review (mean 2.3±2.1 years post-operatively), 92.6% had trivial or no aortic regurgitation. Predictors of post-operative mortality included active endocarditis, acute aortic dissection and peripheral vascular disease. Conclusions We report acceptable short and long term outcomes following FSB implantation in a cohort of comparatively younger patients with thoracic aortic disease. The durability of this bioprosthesis in the younger population remains to be confirmed.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation, affecting 1-2% of the population. BAV is caused by fusion of two of the three aortic valve leaflets in the heart during foetal development. Progressive dilatation of the thoracic aorta, resulting in aneurysm (TAA), develops in approximately 50% of individuals with BAV, and can be fatal. The cause of BAV-TAA is undetermined, however, current understanding suggests that it is a complex interplay between genetic susceptibility and the abnormal haemodynamic stress generated by the malformed valve. Changes in the expression of post-transcriptional genetic modifiers, such as microRNA (miRNA), can alter protein expression and disrupt normal tissue function, contributing to disease. miRNA are also viable therapeutic targets with demonstrated success in disease treatment. We hypothesised that there is altered expression of miRNA in BAV-TAA tissue that contributes to TAA development. Total RNA was isolated from aortic tissue of 11 patients with BAV-TAA (Age 54 ± 12 years; M:F 10:1), and 6 normal controls with no aortic disease (Age 35 ± 18 years; M:F 4:2). RNA was reverse transcribed with primers for 818 different miRNA and qPCR was performed using Taqman® OpenArray® Human miRNA Panels. A significant difference in miRNA expression was defined as a >±2 fold change (p

The shifting global demographic profile toward an older population is well recognized and carries with it the increased burden of degenerative cardiovascular disease, with associated morbidity, mortality, and healthcare costs. Vascular ageing is characterized by increased arterial stiffness, systolic arterial hypertension, myocardial thickening and fibrosis, and associated atherosclerosis.1 See Article by Martinsson et al Calcific aortic valve stenosis (CAVS) is another manifestation and affects ≈1 in 30 people aged 75 years. Furthermore, CAVS is associated with several adverse vascular risk factors, including hypertension, hypercholesterolemia, and diabetes mellitus, as well as with underlying structural abnormalities, for example, bicuspid aortic valve. Considerable resources are already devoted to health care consequent on vascular ageing and the load is increasing—as evidenced by the burgeoning need for operative and percutaneous aortic valve replacements.2 If society is to better manage health costs for the older population, we need to better understand the mechanisms of vascular ageing and thereby develop and implement novel preventive strategies. There is significant familial risk for atherosclerotic vascular disease, beyond familial hypercholesterolemia and hypertension, although the actual genetic factors responsible remain elusive. In this issue of Circulation: Cardiovascular Genetics , Martinsson et al3 present evidence for a significant familial risk for CAVS in the general population. At the same time, there is also a lesser, but nonetheless significant, environmental risk. The fascinating question is how we might explain these observations and whether we can now begin to formulate a hypothesis about why some individuals develop CAVS. A systolic ejection murmur is a common finding in older patients and echocardiography has shown us that most individuals develop some thickening and restriction of leaflet motion of the aortic valve with increasing age. Despite this, most …

Background Composite valve-graft (CVG) replacement of the aortic root is a well-studied and recognised treatment for various aortic root conditions, including valvular disease with associated aortopathy. There have been few previous studies of the procedure in large numbers in an Australian setting. Method From January 2006 to June 2013, 246 successive patients underwent CVG root replacements at our institution. Mean age was 56.8 years, 85.4% were male, and 87 had evidence of bicuspid aortic valve. Indications for operation included ascending aortic aneurysm in 222 patients, annuloaortic ectasia in 67 patients, and aortic dissection in 38 patients. Results The overall unit 30-day mortality was 5.7%, including: elective 30-day mortality of 2.2%, and emergent 30-day mortality of 17.2%. Statistically significant multivariate predictors of 30-day mortality were: acute aortic dissection (OR=20.07), peripheral vascular disease (OR=11.17), new ventricular tachycardia (OR=30.17), re-operation for bleeding (OR=14.42), concomitant mitral stenosis (OR=68.30), and cerebrovascular accident (OR=144.85). Conclusions Low postoperative mortality in our series matches closely with results from similar sized international studies, demonstrating that this procedure can be performed with low risk in centres with sufficient experience in the operative procedure.

We present a patient with Takayasu arteritis and severe aortic valve regurgitation and bilateral carotid artery occlusions, who underwent aortic valve replacement and aorto-bicarotid bypass. The management of the cardiovascular manifestations of Takayasu arteritis is reviewed.

Background Marfan syndrome (MFS) and familial non–syndromal thoracic aortic aneurysm and dissection (ns‐TAAD) are genetic aortopathies causing aortic dilatation with increased aortic stiffness. Left ventricular (LV) contractility and ventricular‐vascular coupling index (VVI) were compared between MFS and ns‐TAAD and determinants of VVI were investigated. Methods and Results Patients with MFS (M 57, F 47) and ns‐TAAD (M 72, F 39) were studied by echocardiography and compared with controls (M 77, F 71). Aortic geometry, hemodynamics, LV work, LV contractility (end‐systolic elastance [E es ]), and VVI were documented. Aortic sinuses were equally dilated in MFS (19.7±2.4) and ns‐TAAD (19.8±1.8) compared to controls (16.2±1.4 mm·m −2 , P P −2 P es was reduced in MFS (1.32±0.19) compared to controls (1.65±0.29 mm Hg·mL −1 , P P P Conclusions Left ventricular contractility and ventricular‐vascular coupling are abnormal in MFS but preserved in ns‐TAAD, and are independent of aortic stiffness, consistent with intrinsic impairment of myocardial contractility in MFS.

Multiple genes are associated with thoracic aortic aneurysm (TAA) formation, including FBN1, TGFBR1&2, COL3A1 & 5A2, and MYH11. Given the population incidence of mutations in these genes we hypothesise that it is likely that ‘double hit’ mutations occur, which may result in an altered clinical phenotype when compared with the single gene mutation. Genomic DNA analysis of 19 genes implicated in TAA was performed on 12 patients with inherited TAA disease. Of the patients analysed, one patient (P1) was identified as having a mutation in both MYH11 (c.2517G.C (pW839C)) and FBN1 (splice donor site c.4210+1G>A). Another patient (P2) was identified as having both COL5A2 (c.3794A>G (pD1265G)) and FBN1 (c.5861T>G (p.F1954C)). All mutations were predicted by PolyPhen to be deleterious. P1 has Marfan Syndrome (MFS), caused by the FBN1 mutation, and has severe aortic dilatation while his mother (M1), who also has MFS but does not have the MHY11 mutation, developed mild aortic dilatation, suggesting that the MHY11 mutation in P1 has resulted in a more aggressive phenotype. P2, siblings S1 and S2 and father (F2) all have relatively less severe MFS with progressive moderate dilatation of the aorta. Thus, the phenotype of pedigree 2 is similar for all affected members, but only P2 has a double hit mutation, suggesting that the presence of the COL5A2 mutation in P2 has not altered the clinical phenotype. This is the first instance where double hit mutations have been described in inherited thoracic aortic aneurysm but the effect of multiple mutations on phenotype appears to be variable. Mutation analysis for individuals with inherited thoracic aortic aneurysm should consider the possibility of multiple gene culprits.

Background— The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. Methods and Results— The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2 . Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. Conclusions— Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.

Objectives This systematic review and meta-analysis was performed to evaluate the impact of pre-operative atrial fibrillation (preAF) on early and late outcomes after coronary artery bypass graft (CABG) surgery. Methods Medline, EMBASE and CENTRAL were systematically searched for studies that reported CABG outcomes according to the presence or absence of preAF. Data were independently extracted by two investigators; a meta-analysis was conducted according to predefined clinical endpoints. A subgroup analysis was performed based on revascularization strategy (off-pump or on-pump CABG). Results Twelve observational studies (n=389,998) met criteria for inclusion, with eight studies (n=381,479) reporting propensity-matched or adjusted analyses. Peri-operative mortality was higher overall in patients with preAF (odds ratio [OR] 1.64; 95% confidence interval [CI], 1.29–2.09; p Conclusion PreAF portends poorer peri-operative and long-term outcomes in patients undergoing CABG, regardless of revascularization strategy.

Nitric oxide (NO) may modulate myocardial ischaemia/reperfusion (I/R) injury, but effects of hypercholesterolaemia on myocardial NO release during I/R are unknown.A NO-specific carbon fibre electrode continuously measured coronary sinus [NO] during 60 min low-flow ischaemia (1 ml/min) and 60 min free reperfusion (I/R) in isolated rabbit hearts. Experimental groups (n=7 per group) were control, L-arginine supplement (200 microM), N-nitro-L-arginine methyl ester (L-NAME) treatment (8 microM) and hypercholesterolaemic.During early I, NO release decreased markedly in control (-1356+/-286 pmol/min/g) and L-arginine (-1972+/-172) groups, but less in L-NAME (-441+/-89) and hypercholesterolaemic (-602+/-164) groups (both p0.01 vs. controls). No increase in NO release during I was seen in any group. After R, NO release increased above baseline in control (+2333+/-591 pmol/min/g) and L-arginine (+1048+/-278) groups and hypercholesterolaemic (+1100+/-478) (p0.05 vs. pre-ischaemia each group). There was little increase in NO release in the L-NAME group (+436+/-247 pmol/min/g, p0.05 vs. controls). In each group, myocardial NO release declined towards pre-ischaemic levels during 60 min R. Hearts treated with L-arginine had similar NO release but better functional recovery than controls (p0.01). Treatment with L-NAME was also associated with better functional recovery than in controls or hypercholesterolaemic hearts.Myocardial NO release declines rapidly during ischaemia, but increases above baseline during early reperfusion. Improved function after L-arginine treatment appears to be independent of effects upon NO release. Hypercholesterolaemia is associated with reduced myocardial NO release, under both baseline conditions and during ischaemia and reperfusion.

A brief period of ischemia followed by timely reperfusion may lead to prolonged, yet reversible, contractile dysfunction (myocardial stunning). Damage to the myocardium occurs not only during ischemia, but also during reperfusion, where a massive release of oxygen-free radicals (OFR) occurs. We have previously utilized 2-DE and MS to define 57 protein spot changes during brief ischemia/reperfusion (15 min ischemia, 60 min reperfusion; 15I/60R) injury in a rabbit model (White, M. Y., Cordwell, S. J., McCarron, H. C. K., Prasan, A. M. et al., Proteomics 2005, 5, 1395-1410) and shown that the majority of these occur because of physical and/or chemical PTMs. In this study, we subjected rabbit myocardium to 15I/60R in the presence of the OFR scavenger N-(2-mercaptopropionyl) glycine (MPG). Thirty-seven of 57 protein spots altered during 15I/60R remained at control levels in the presence of MPG (15I/60R + MPG). Changes to contractile proteins, including myosin light chain 2 (MLC-2) and troponin C (TnC), were prevented by the addition of MPG. To further investigate the individual effects of ischemia and reperfusion, we generated 2-DE gels from rabbit myocardium subjected to brief ischemia alone (15I/0R), and observed alterations of 33 protein spots, including 18/20 seen in both 15I/60R-treated and 15I/60R + MPG-treated tissue. The tissue was also subjected to ischemia in the presence of MPG (15I/0R + MPG), and 21 spot changes, representing 14 protein variants, remained altered despite the presence of the OFR scavenger. These ischemia-specific proteins comprised those involved in energy metabolism (lactate dehydrogenase and ATP synthase alpha), redox regulation (NADH ubiquinone oxidoreductase 51 kDa and GST Mu), and stress response (Hsp27 and 70, and deamidated alpha B-crystallin). We conclude that contractile dysfunction associated with myocardial stunning is predominantly caused by OFR damage at the onset of reperfusion, but that OFR-independent damage also occurs during ischemia. These ischemia-specific protein modifications may be indicative of early myocardial injury.

Increased cardiac output in pregnancy is associated with cardiac remodeling and possible reduction in contractility, which may worsen in preeclampsia. Left ventricular (LV) geometry and function were compared between nonpregnant controls ( n = 12) and normotensive ( n = 44) and preeclamptic ( n = 15) pregnant women using echocardiography. Load-independent comparisons of LV systolic function compared end-systolic stress (ESS) and rate-corrected velocity of circumferential fiber shortening ( VCFC). Mean arterial pressures were 101 ± 14 mmHg in preeclampsia, 76 ± 6 mmHg in normotensive pregnancy, and 78 ± 6 mmHg in controls ( P < 0.005 vs. preeclampsia). LV mass increased during normotensive pregnancy (66 ± 13 to 76 ± 16 g/m2; P < 0.05; controls, 65 ± 10 g/m2; P < 0.05) and was greater in preeclampsia (90 ± 18 g/m2; P < 0.05). In normotensive pregnancy, ESS decreased (59 ± 9 to 52 ± 11 g/cm2; P < 0.05; controls, 66 ± 14 g/cm2; P < 0.005). ESS was greater in preeclampsia (60 ± 14 g/cm2; P < 0.05). In controls, there was an inverse relationship between ESS and VCFC( r = −0.78). The ESS- VCFCrelationships in normotensive and preeclamptic pregnancy were unchanged from controls. We conclude that LV hypertrophy in normotensive and preeclamptic pregnancy matches changes in cardiac work, and LV contractility is preserved.

It has been hypothesised that activation of matrix metalloproteinase-2 (MMP-2) contributes to reversible myocardial dysfunction (stunning) following short-term ischaemia and reperfusion. Gelatin zymography was used to measure release of both pro-MMP-2 (72 kDa) and MMP-2 (62 kDa), into the coronary effluent from isolated, perfused rabbit hearts during 90 min aerobic perfusion (control), or low-flow ischaemia (15 or 60 min at 1 mL/min), followed by 60 min reperfusion. In controls, pro-MMP-2 was detected in the coronary effluent throughout the first 30 min of aerobic perfusion, but MMP-2 was not detected. In contrast, MMP-2 was detected in the coronary effluent during reperfusion after both 15 and 60 min ischaemia. However, while left ventricular systolic function was impaired after both 15 min and 60 min ischaemia, a significant increase in the release of MMP-2 was only detected in hearts following 60 min ischaemia. The dissociation between mechanical function and MMP-2 levels suggest that MMP-2 does not contribute to myocardial stunning in this model, but may contribute to myocardial dysfunction following prolonged ischaemia.

Nitric oxide (NO)-mediated and NO-independent mechanisms of endothelium-dependent vasodilatation involve Ca2+-dependent K+ (KCa) channels. We examined the role in vivo of KCa channels in NO-independent vasodilatation in hypercholesterolemia. Hindlimb vascular conductance was measured at rest and after aortic injection of ACh, bradykinin (BK), and sodium nitroprusside in anesthetized control and cholesterol-fed rabbits. Conductances were measured before and after treatment with the NO synthase antagonist N ω-nitro-l-arginine methyl ester (l-NAME, 10 mg/kg) or KCa blockers tetraethylammonium (30 mg/kg), charybdotoxin (10 μg/kg), and apamin (50 μg/kg). The contribution of NO to basal conductance was greater in control than in cholesterol-fed rabbits [2.2 ± 0.4 vs. 1.1 ± 0.3 (SE) ml · min−1 · kg−1 · 100 mmHg−1, P < 0.05], but the NO-independent KCa channel-mediated component was greater in the cholesterol-fed than in the control group (1.1 + 0.4 vs. 0.3 ± 0.1 ml · min−1 · kg−1 · 100 mmHg−1, P < 0.05). Maximum conductance response to ACh and BK was less in cholesterol-fed than in control rabbits, and the difference persisted after l-NAME (ACh: 7.7 ± 0.7 vs. 10.1 ± 0.5 ml · min−1 · kg−1 · 100 mmHg−1, P < 0.005). Blockade of KCa channels with tetraethylammonium or charybdotoxin + apamin almost completely abolished l-NAME-resistant vasodilatation after ACh or BK. The magnitude of KCa-mediated vasodilatation after ACh or BK was impaired in hypercholesterolemic rabbits. Vasodilator responses to nitroprusside did not differ between groups. In vivo , hypercholesterolemia is associated with an altered balance between NO-mediated and NO-independent KCa channel contributions to resting vasomotor tone and impairment of both mechanisms of endothelium-dependent vasodilatation.

Objective To determine whether placental vascular endothelial growth factor (VEGF) is increased in pre-eclampsia. Design Prospective cohort study. Setting Royal Prince Alfred Hospital, Sydney, Australia. Sample Eleven normotensive women and eight women with pre-eclampsia matched for age and gestation. Methods Uterine artery Doppler ultrasound flow velocity profiles were recorded in the third trimester and resistance index calculated as (Vs-Vd)/Vs (Vs= peak systolic flow velocity, Vd= end diastolic flow velocity). Placental tissue at delivery was examined for VEGF distribution with avidin-biotin-peroxidase immunohistochemistry. Results Uterine resistance index [median (range)] was significantly increased in pre-eclamptic women (normotensive: 0.42 (0.36–0.51); pre-eclampsia: 0.59 (0.40–0.75); P= 0.005). Notching of the uterine artery waveform, consistent with a high resistance circulation, was evident in early diastole in five women with pre-eclampsia but only one normotensive woman (P= 0.013). Placental VEGF was increased in women with pre-eclampsia in the decidual trophoblast (normotensive: 34% (4–59) cells stained for VEGF; pre-eclampsia: 58% (15–95); P= 0.033) and in the villous syncytiotrophoblast (normotensive: VEGF count 1.4 arbitrary units (1.1–2.1); pre-eclampsia: 1.8 arbitrary units (1.4–2.2); P= 0.041). Analysis indicated that uterine artery resistance index was directly correlated with placental VEGF staining, mean arterial pressure and birthweight. Conclusions Abnormal uterine artery Doppler ultrasound flow velocity profiles in pre-eclampsia indicate increased uteroplacental resistance. The associated increase in placental VEGF may represent a compensatory mechanism attempting to restore blood flow towards normal.

Hypertrophic cardiomyopathy (HCM) is associated with mutations of genes coding for major sarcomeric proteins, but the mechanism of hypertrophy is unknown. As hypertrophy may not develop until adolescence, an altered response to physiological growth stimuli may regulate the hypertrophy process.This study examined the relationship between age and changes in left ventricular (LV) wall thickness in patients with HCM.Forty-three patients who had definite electrocardiographic and echocardiographic evidence of HCM were studied with serial 2D and M-mode echocardiograms at least two years apart (mean interval 5.5 +/- 3.0 years). LV cavity dimensions, septal and posterior wall thicknesses, and LV mass indices were compared with data from an age- and gender-matched control group.In patients with HCM aged ten to 20 years (n = 9), there was an increase in septal wall thickness during the study period from 15.9 +/- 6.2 mm to 19.3 +/- 2.1 mm (p0.01). This increase (3.4 +/- 2.5 mm) greatly exceeded the change in septal thickness observed in the control group between the ages of ten and 20 years (0.8 +/- 0.3 mm, p0.01). There was a lesser increase in posterior wall thickness from 9.8 +/- 2.1 mm to 11.5 +/- 3.5 mm (p = 0.07). In patients with HCM aged 21-40 years (n = 11), there was also an increase in septal wall thickness during the study period from 16.0 +/- 2.2 mm to 17.8 +/- 3.0 mm (p0.05), but no change in septal thickness in the control group. In contrast, the patients aged40 years (n = 23) showed no significant change in either septal or posterior wall thickness during the study period. LV mass index increased in the ten to 20 years age group from 128 +/- 24 g/m2 to 164 +/- 20 g/m2 (p = 0.01), but this increase was not observed in the older age groups.LV hypertrophy is progressive, particularly in the septum, during adolescence and early adult life in patients with HCM. As progressive hypertrophy may continue after somatic growth has ceased, an abnormal myocardial response to physiological growth regulators is less likely to be the principal stimulus to hypertrophy. Gene-gene interactions, changes in haemodynamic load or environmental factors may modulate the development of hypertrophy. Serial measurements of ventricular wall thickness in the first two decades of life, and probably until the fourth decade of life are advisable in patients suspected of having HCM.

Background The Medtronic Freestyle bioprosthesis (FSB) provides an alternative to other prostheses for both aortic valve and aortic root surgery. This paper is a systematic review of the post-operative outcomes in patients with aortic valve and/or aortic root disease following FSB implantation. Methods Electronic databases were searched for primary analysis, prospective randomised studies comparing the FSB with an alternative aortic prosthesis were included. Additionally, case series that included data for at least 100 individual operated patients were used for secondary analysis. Results Among three identified randomised studies, 199 FSB cases were compared with homografts, and stented and an alternative stentless bioprosthesis. The FSB showed comparable hospital mortality (4.5% vs 5.3%) and eight-year actuarial survival (80 ± 5.0% versus 77 ± 6.0%) with the homograft (respectively) and comparable reduction in left ventricular mass index relative to other prosthesis types. Over 6000 individual patients were included in the selected 15 case series. Weighted mean operative mortality, neurological event rate and five-year actuarial survival was 5.2%, 5.5% and 77.8%, respectively. Conclusion The FSB performed comparably against alternative prostheses regarding in-hospital mortality, long-term survival and reduction in left ventricular mass index. Included case series demonstrated robust post-operative outcomes in both the short and long term.

Objectives.We examined the utility of the 32-point QRS score from the 12-lead electrocardiogram (ECG) for measurement of the ischemic risk region and infarct size in patients receiving thrombolytic therapy.Background.The QRS score offers a means of evaluating the therapeutic benefit of thrombolytic therapy by comparing final infarct size with the initial extent of ischemic myocardium.Methods.The study included 38 patients (34 men, 4 women; mean [±SD] age 54 ± 10 years) with a first infarction (18 anterior, 20 inferior). The maximal potential QRS score (QRS0) was assigned to all leads with ≥ 100-μV ST elevation on the initial ECG. The QRS scores were calculated at 7 and 30 days after infarction. Left ventricular ejection fraction was measured by radionuclide ventriculography at 1 month. Twenty-eight patients had thallium (T1)-201 and technetium (Tc)-99m pyrophosphate tomographic measurement of the ischemic region and infarct size.Results.The QRS0was 10.3 ± 3.1 (mean ± SD) for anterior and 10.4 ± 3.5 for inferior infarcts. The QRS scores were similar at 7 and 30 days for both anterior (5.6 ± 3.4 vs. 5.5 ± 3.4) and inferior infarcts (3.7 ± 2.6 vs. 2.9 ± 2.2). The day 7 QRS score and ejection fraction at 1 month were inversely correlated (r = −0.74, p < 0.01). The T1-201 perfusion defect was 34 ± 11% of the left ventricle for anterior and 32 ± 7% for inferior infarcts. Subsequent Tc-99m pyrophosphate infarct size was 15 ± 9% of the left ventricle for anterior and 17 ± 9% for inferior infarcts. The QRS0was correlated with the extent of the T1-201 perfusion defect (r = 0.79, p < 0.001), and the day 7 QRS score was correlated with Tc-99m pyrophosphate infarct size (r = 0.79, p < 0.005).Conclusions.The 32-point QRS score can provide useful immediate measurements of the ischemic risk region and subsequent infarct size.

This study compared aortic biomechanics in different heritable aortopathy syndromes and examined the clinical utility of aortic stiffness measurements.In 218 patients (55 Marfan, 47 bicuspid aortic valve (BAV), 47 isolated familial thoracic aneurysm (FTAD) and 69 matched controls) aortic biomechanics were measured by echocardiography with simultaneous blood pressure measurements. Patients were stratified by age as ≤40 years or40 years. Aortic stiffness increased with age and aortic biomechanics were abnormal in all aortopathies, particularly in BAV and FTAD. Increased stiffness and pulse wave velocity were seen in BAV and FTAD in both age cohorts (p0.001) and both were stiffer than Marfan patients (p0.01). Marfan patients aged ≤40 years had stiffer aortas than controls, but those40 years were similar to controls. Multivariate regression identified age as the dominant correlate with increased stiffness, and also aortic diameter and mean blood pressure (R(2)=0.64; p0.001). Aortopathy patients with stiffness index16 had lower rate of increase in aortic diameter (0.25±0.30 mm/year) than those with normal stiffness (0.68±0.39 mm/year, p0.001). Whilst positive predictive value of increased stiffness for detection of aortopathy was high (93% in age≤40 years, 87%, in age40 years), negative predictive accuracy was low (55% and 34% respectively).Abnormal biomechanics are common to all aortopathies, with greater abnormality in BAV and FTAD than in Marfan. Increased aortic stiffness is associated with slower rate of aneurysm progression.

This study examined the relations between age, arterial distensibility, and systemic hemodynamics in patients with the Marfan syndrome. The study group included 170 patients referred to a specialist clinic, of whom 55 (age 26 +/- 12 years) were diagnosed as having Marfan syndrome. The remaining 115 patients (age 25 +/- 14 years) formed a control group. Each patient underwent echocardiographic examination, with measurement of ascending aorta diameter at end-diastole and end-systole, and aortic flow velocities. The elastic properties of the aorta were indexed by calculation of aortic distensibility, wall stiffness, and systemic pulse wave velocity. Mean end-diastolic aortic diameter in the Marfan group (38 +/- 9 mm) was greater than that in the controls (26 +/- 4 mm, p < 0.01). Resting heart rate and aortic flow velocities were similar in the 2 groups, but systemic arterial pulse pressure was greater in the Marfan group (50 +/- 12 mm Hg) than in the controls (41 +/- 8 mm Hg, p < 0.01). Aortic diameter increased with age in both groups, but at all ages the Marfan group exhibited greater aortic diameters (p < 0.05). Aortic distensibility was less in the Marfan group (2.6 +/- 1.3 cm2.dynes-1 x10(-6)) than in the controls (6.2 +/- 2.1 cm2.dynes-1 x 10(-6), p < 0.01), and the aortic wall stiffness index was greater in the Marfan group (7.9 +/- 3.4) than in the controls (2.8 +/- 0.6, p < 0.01). Aortic wall stiffness increased with age and aortic diameter, but at all ages the Marfan group exhibited a stiffer aorta for a given diameter than did the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Contrast angiography provides a silhouette of the arterial lumen, but does not give information about arterial wall structure. Catheter-tip ultrasound transducers can now provide a cross-sectional image of the arterial wall. This study examined the pathological correlation of intravascular ultrasound images and the accuracy of ultrasound measurements of vascular geometry. Methods: Intravascular ultrasound images were obtained with a mechanically rotated catheter-tip transducer and recorded on videotape. Initial validation studies were performed in fresh, postmortem arterial specimens, which were filled with saline at physiological pressures. Ultrasound images at specific sites were compared with the pathological findings at that site and measurements of luminal diameter were compared with corresponding angiographic measurements. Subsequently, intravascular ultrasound was employed to examine the aorta, ilio-femoral and coronary arteries in patients undergoing balloon angioplasty. Results: The pathological correlations showed that intravascular ultrasound can detect early initial thickening and mild atherosclerotic lesions that do not result in luminal deformation. Ultrasound images provided definition of calcified, fibrotic and lipid-filled lesions. Ultrasound measurements of luminal diameter correlated well with pathology measurements (r = 0.93), as did ultrasound measurements of plaque area (r = 0.89). The in vivo studies demonstrated that intravascular ultrasound can define atheroma lesions not evident on contrast angiography and permits detailed evaluation of the results of interventions such as balloon angioplasty. Conclusions: Intravascular ultrasound provides a unique window upon arterial structure and pathology in humans. Ultrasound images allow accurate measurements of vascular geometry and define early atheromatous lesions that are not evident with angiography.

Early definition of treatment outcomes, including coronary patency and infarct size, after reperfusion therapy for myocardial infarction (MI) is desirable to identify patients requiring further intervention.Patients receiving reperfusion therapy for a first MI had continuous 12-lead ST segment monitoring to document reperfusion and ischaemia time. Infarct size was measured by 12-lead QRS score and radionuclide scintigraphy ((201)Tl single-photon emission computed tomography, SPECT) at 1 week, and left ventricular function by echocardiography at 1 week and 1 month. Resolution of ST elevation accurately detected TIMI 2 or 3 reperfusion (predictive accuracy 93%) in 55 patients undergoing immediate angioplasty, but ST recovery was delayed (17+/-14min) after angiographic reperfusion. A multivariate model, including risk region and ischaemia time, accurately predicted MI size (R(2)=0.80, P0.00001) in these patients. The same model, prospectively applied on Day 1 to 154 patients receiving thrombolytic therapy, accurately predicted MI size, measured by QRS score (R(2)=0.88, P0.0000001) and (201)Tl SPECT (R(2)=0.75, P0.000001) at 1 week for individual patients. Regional myocardial wall motion at 1 month was directly correlated with MI size predicted by the model on Day 1 (r=0.73, P0.0001).Use of ST segment monitoring during reperfusion therapy facilitates early prediction of treatment outcomes, including coronary reperfusion, infarct size and ventricular function.

A recent article in the British Medical Journal raised important questions about professional transparency, the collection and use of outcome data and the respective roles of professional societies, commissioners of care, regulators and politicians.1 Professional societies have traditionally been viewed both internally and externally as existing largely for the benefit of their members in providing a forum for education and scientific exchange as well as focus for interaction with other professional organisations and with various regulatory bodies.2 This perception has evolved with the increasing involvement of large international societies in the development of guidelines for the delivery of cardiology care. The mission statement of the European Society of Cardiology is to reduce the burden of cardiovascular disease in Europe, that of the American College of Cardiology to transform cardiovascular care and improve heart health and that of the British Cardiovascular Society to promote excellence in cardiovascular care. These are sweeping and ambitious aims and extend much further than the provision of education and the writing of practice guidelines, essential as these activities are. Regulators are becoming more interested in the continuing competence of medical staff. In the UK medical revalidation is just beginning with the explicit aim of assuring patients and the public, employers and other healthcare professionals that licensed doctors are up to date and fit to practice.3 Revalidation is about defining acceptable practice, not excellence, and the expectation is that the vast majority of doctors will pass muster. In the US physicians must complete Maintenance of Competence (MOC) over a 10-year cycle including self-evaluation of medical knowledge and practice performance and an exam.4 Modern medical professionalism extends beyond competence and mandates that doctors keep the needs of patients paramount and view their service through their patients’ eyes. All patients deserve good doctors but what …

Effects of ischemia time and treatment interventions upon troponin I (TnI) proteolysis and function of reperfused myocardium were examined in isolated, perfused rabbit hearts. Hearts were randomized to 90 min aerobic perfusion, 15 min low-flow (1 ml/min) ischemia (I) and 60 min reperfusion (R) or 60 min low-flow I and 60 min R. Hearts subject to 60 min I and 60 min R received either no treatment, l -arginine treatment, or treatment with oxygen free radical (OFR) scavengers (mercapto-proponyl-glycine, catalase and superoxide dismutase). Hearts from cholesterol-fed rabbits were also studied after 60 min I and R. Isovolumic LV pressure and heart rate were recorded throughout and Western analysis of ventricular myocardium, using 3 specific antibodies, detected intact TnI (29 kDa) and TnI fragment (25 kDa). Hearts subject to 15 min I had minimal irreversible injury (TTC negative region=0.6+/-0.4% LV) but hearts subject to 60 min I had more extensive injury (TTC negative=40.7+/-5.8% LV). Recovery of rate-pressure product after 15 min I and 60 min R (56+/-9% of baseline) was better than after 60 min I and 60 min R (23+/-9%, P