Rio Aguilar

Impact of contrast-enhanced echocardiography on the diagnostic algorithm of acute aortic dissection

AIMS To determine the usefulness of contrast echocardiography in the diagnosis of aortic dissection (AD) and in the assessment of findings necessary for adequate patient management. METHODS AND RESULTS Conventional and contrast-enhanced transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE) were performed in 128 consecutive patients with clinically suspected acute AD. Results were validated independently against intraoperative findings in 45 patients and computed tomography information in 83. Sensitivity and specificity of conventional TTE increased after contrast enhancement from 73.7 to 86.8% (P< 0.005) and 71.2 to 90.4% (P < 0.05), respectively. Sensitivity and specificity of enhanced TTE were similar to conventional TOE in ascending aorta (93.3 vs. 95.6% and 97.6 vs. 96.4%, respectively) and in the arch (88.4 vs. 93.0% and 95.3 vs. 98.82%, respectively). Contrast-enhanced TOE permitted the location of non-visualized entry tear in seven cases (10.6%), helped to correctly identify the true lumen in six (9.1%), and diagnosed retrograde dissection in nine (13.6%). CONCLUSION Contrast enhancement substantially improves TTE in the diagnosis of AD and should be considered as the initial imaging modality in the emergency setting. Contrast enhancement also has significant value for obtaining critical morphological and haemokinetic information by TOE useful for adequate patient management.

Effects of substitution of Cx43 by Cx32 on myocardial energy metabolism, tolerance to ischaemia and preconditioning protection.

Connexin 43 (Cx43) plays an important role in cardioprotective signalling by mechanisms at least in part independent of gap junctional communication. To investigate whether this role is related to specific properties of this connexin isoform, we used a knock‐in mouse model in which the coding region of Cx43 is replaced by that of Cx32. Homozygous Cx43KI32 mice showed reduced cell‐to‐cell Lucifer Yellow transfer (P < 0.01), but QRS duration and left ventricular fractional shortening (echocardiography) were similar to those in wild‐type animals. NMR spectroscopy detected reduced ATP and increased lactate content in myocardium from homozygous Cx43KI32 animals (P < 0.05). Despite this, isolated homozygous Cx43KI32 hearts showed smaller infarcts after ischaemia–reperfusion (40 min/60 min) as compared to hearts from heterozygous and wild‐type animals (13 and 31% reduction, respectively, P < 0.05). Cardiac myocytes isolated from Cx43KI32 mouse hearts also showed a reduced rate of cell death after simulated ischaemia–reperfusion. In a separate series of experiments, both ischaemic (4 cycles of 3.5 min of ischaemia and 5 min of reperfusion) and pharmacological (50 μmol l−1 diazoxide, 10 min) preconditioning reduced infarct size in hearts from wild‐type mice (by 24.84 and 26.63%, respectively, P < 0.05), but only ischaemic preconditioning was effective in hearts from heterozygous animals and both preconditioning strategies failed to protect Cx43KI32 homozygous hearts. These results demonstrate that Cx43 has an important and previously unknown modulatory effect in myocardial energy metabolism and tolerance to ischaemia, and plays a critical role in preconditioning protection, by mechanisms that are specific for this connexin isoform.

Constitutive COX-2 activity in cardiomyocytes confers permanent cardioprotection: Constitutive COX-2 expression and cardioprotection

Different lines of evidence suggest that inhibition of COX-2 activity exacerbates reperfusion injury, but direct data showing beneficial effects of increased COX-2 activity are lacking. The aim of this study was to determine the effect of constitutive expression of COX-2 on cardiomyocyte tolerance to ischemia-reperfusion injury. We generated a transgenic mouse (B6D2-Tg (MHC-PTGS2)17Upme) that constitutively expresses functional human COX-2 in cardiomyocytes under the control of alpha-myosin heavy chain promoter. COX-2 expression was confirmed by immunoblotting and by increased levels of PGE(2) and PGI(2) in myocardium. Histological and echocardiographic analysis revealed no differences in the phenotype of transgenic mice (TgCOX-2) with respect to wild type (Wt) mice. Tolerance to ischemia-reperfusion injury was analysed in a Langendorff system. Reperfused TgCOX-2 hearts after 40 min of ischemia improved functional recovery (32.9+/-6.2% vs. 9.45+/-4.4%, P=0.004) and reduced cell death assessed by LDH release (43% of reduction, P<0.001) and triphenyltetrazolium staining (41% of reduction, P=0.002). Cardioprotection was not further increased by ischemic preconditioning. Pretreatment of mice with the COX-2 inhibitor DFU attenuated cardioprotection with a correlation between myocardial PGE(2) levels and the extent of cell death. NMR spectroscopy showed a marked reduction in arachidonic acid (AA) content in TgCOX-2 hearts. Both, DFU pretreatment and perfusion of TgCOX-2 hearts with AA increased myocardial AA to values similar to those measured in Wt hearts and reversed cardioprotection. We conclude that constitutive expression of COX-2 in cardiomyocytes confers a permanent cardioprotective state against reperfusion injury. Increased PGE(2) synthesis and reduced AA content could explain this effect.

Specific Targeting of Human Inflamed Endothelium and In Situ Vascular Tissue Transfection by the Use of Ultrasound Contrast Agents

OBJECTIVES We used human umbilical cord segments as an ex vivo model to investigate the possible clinical diagnostic and therapeutic applications of microbubbles (MBs). BACKGROUND Microbubbles are commonly used in clinical practice as ultrasound contrast agents. Several studies have addressed the in vivo applications of MBs for specific targeting of vascular dysfunction or sonoporation in animal models, but to date no human tissue model has been established. METHODS Primary venular endothelial cell monolayers were targeted with MBs conjugated to an antibody against a highly expressed endothelial marker (tetraspanin CD9), and binding was assessed under increasing flow rates (0.5 to 5 dynes/cm(2)). Furthermore, CD9-coupled MB endothelial targeting was measured under flow conditions by contrast-enhanced ultrasound analysis in an ex vivo human macrovascular model (umbilical cord vein), and the same tissue model was used for the detection of inflamed vasculature with anti-intercellular adhesion molecule (ICAM)-1-coated MBs. Finally, plasmids encoding fluorescent proteins were sonoporated into umbilical cord vessels. RESULTS Specific endothelial targeting in the in vitro and ex vivo models described previously was achieved by the use of MBs covered with an anti-CD9. Furthermore, we managed to induce inflammation in umbilical cord veins and detect it with real-time echography imaging using anti-ICAM-1-coupled MBs. Moreover, expression and correct localization of green fluorescent protein and green fluorescent protein-tagged ICAM-1 were assessed in this human ex vivo model without causing vascular damage. CONCLUSIONS In the absence of clinical trials to test the benefits and possible applications of ultrasound contrast agents for molecular imaging and therapy, we have developed a novel ex vivo human model using umbilical cords that is valid for the detection of inflammation and for exogenous expression of proteins by sonoporation.

Usefulness of real-time three-dimensional transoesophageal echocardiography in the assessment of chronic aortic dissection

AIMS To assess the usefulness of three-dimensional transoesophageal echocardiography (3D-TOE) vs. two-dimensional (2D)-TOE in the evaluation of morphological and dynamic findings of aortic dissection, and compare the results with those obtained by multi-slice computed tomography (CT). METHODS AND RESULTS Twenty-six patients (21 men and 5 women, median age: 67 years, range: 28-74 years) diagnosed of chronic aortic dissection with patent false lumen were studied. A comprehensive 2D-TOE and a real-time 3D-TOE study targeted at assessing dissection variables were performed and compared with CT within 3 months. Both 3D-TOE and 2D-TOE visualized the intimal flap extension and presence of flow in aortic dissection lumina in the same aortic segments. Three-dimensional TOE correctly identified true lumen in all cases, being superior to 2D-TOE in three cases with a spiroidal course of the dissection in descending aorta. Maximum entry tear diameter measured by 3D-TOE showed a better correlation with CT than 2D-TOE (0.96 and 0.87, P< 0.001, respectively). Compared with CT, 2D-TOE underestimated maximum entry tear diameter (-1.75 ± 3.28 mm, P< 0.01) but 3D-TOE did not (-0.20 ± 1.92 mm, P: n.s.). However, entry tear area measured by 3D-TOE and CT showed the best correlation (r: 0.97) and agreement (0.05 ± 0.20 cm(2), P: n.s.). CONCLUSION Three-dimensional TOE provides additional information to 2D-TOE in aortic dissection assessment, particularly in entry tear size quantification. Agreement between entry tear area defined by 3D-TOE and CT was excellent. Three-dimensional TOE permits better morphological and dynamic understanding of aortic dissection when the flap is spiroidal.

Spanish Acute Aortic Syndrome Study (RESA). Better Diagnosis Is Not Reflected in Reduced Mortality

INTRODUCTION AND OBJECTIVES Because acute aortic syndrome (AAS) is associated with high mortality, early diagnosis and treatment are vital. The aim of the Spanish Acute Aortic Syndrome Study (RESA) was to investigate the effectiveness of current treatment of AAS in a broad range of tertiary care hospitals in Spain. METHODS Between January 2005 and December 2007, 24 tertiary care hospitals reported data on 519 patients with AAS (78% male, mean age 61 +/- 13 years, range 20-92 years): 357 had type-A AAS and 162 had type B. RESULTS The time delay between symptom onset and diagnosis was <24 hours in 67% of cases and >72 hours in 11%. Some 80% of patients with type-A AAS were treated surgically. The interval between diagnosis and surgery was <24 hours in 90% of cases. In patients with type-B AAS, 34% received invasive treatment: 11% had surgery and 23% underwent endovascular procedures. Mortality during hospitalization in patients with type-A disease was 33% in those treated surgically and 71% in those treated medically. Mortality in patients with type-B disease was 17% with medical treatment, 27% with endovascular treatment and 50% with surgical treatment. CONCLUSIONS Despite significant advances in the diagnosis of AAS, in-hospital mortality remains high. The findings of this study are representative of a broad range of unselected patients undergoing treatment for the disease and support the need for continuing improvements in therapeutic approaches to AAS.

Acute absolute vasodilatation is associated with a lower vascular wall stiffness in pulmonary arterial hypertension

BACKGROUND Acute vasoreactivity testing (VT) is considered mandatory in the diagnostic work-up of patients with pulmonary arterial hypertension (PAH). We studied the relation between the acute absolute arterial vasodilatation and the severity of vascular remodeling estimated by intravascular ultrasound (IVUS) in patients with idiopathic PAH. METHODS Simultaneous right heart catheterization and IVUS of the pulmonary artery (PA) were performed both in basal conditions and during short-term intravenous epoprostenol infusion in nineteen idiopathic PAH patients. Pulmonary vascular resistance (PVRi) and capacitance indexes (stroke volume/pulse pressure, Cp), were calculated. Local pulsatility was estimated by IVUS (IVUSp) (systolic-diastolic lumen area/diastolic lumen area×100; sA-dA/dA) and PA stiffness was assessed by the elastic modulus (E: pulse pressure/IVUSp). RESULTS Epoprostenol infusion (11±2ng/kg/min) determined a real vasodilatation (increment of dA>10%) in six patients. This vasodilation group presented on average significantly higher cardiac index, stroke volume index and Cp, and lower PVRi and IVUSp (P<0.05), with a lower E (P=0.08). Three patients were responders according to the actual criteria, but only one showed a real vasodilator response. Baseline E below the median value (≤190mm Hg) was able to differentiate patients with an acute vasodilator response (sensibility 83%, specificity 73%, area under ROC 0.81; P<0.05). Neither E nor vasodilator response is correlated with delta mean PA pressure and PVRi. CONCLUSIONS Patients with higher IVUSp and lesser E displayed an absolute PA vasodilation during VT with epoprostenol. The patients with a positive VT according to actual criteria do not necessarily have a real vasodilatation on intravascular ultrasound.

In vivo assessment of pulmonary arterial wall fibrosis by intravascular optical coherence tomography in pulmonary arterial hypertension: a new prognostic marker of adverse clinical follow-up.

Background: The aim is to correlate pulmonary arterial (PA) remodeling estimated by PA fibrosis in PA hypertension (PAH) with clinical follow-up. Histology of PA specimens is also performed. Methods: 19 patients, aged 54±16 (4 men), functional class II-III were studied with right heart catheterization, PA Intravascular Ultrasound and optical coherence tomography (OCT) in inferior lobe segment. PA wall fibrosis was obtained by OCT ( area of fibrosis/PA cross sectional area × 100). Patients follow-up was blind to OCT. Events were defined as mortality, lung transplantation, need of intravenous prostaglandins or onset of right ventricular failure. Results: OCT measurements showed high intra- and interobserver agreement. There was a good correlation between OCT and histology in PA fibrosis from explanted lungs. Area of fibrosis was 1.4±0.8 mm2, % fibrosis was 22.3±8. Follow-up was 3.5 years (2.5-4.5). OCT %Fib was significantly correlated with PA capacitance (r=-0.536) and with pulmonary vascular rsistance (r=0.55). Patients were divided according to the median value of PA fibrosis. There were 10 patients with a high (≥ 22%) and 9 with a low fibrosis (<22%). Events occurred in 6 (1 death, 1 lung transplantation, 2 intravenous prostaglandins, 2 right heart failure) out of 10 patients with high and in 0 out of 9 patients with low fibrosis (p<0.01). Conclusions: In PAH, the severity of PA remodeling assessed by OCT wall fibrosis was significantly predictive of severely unfavorable clinical outcome. In vivo assessment of pulmonary arterial wall fibrosis by intravascular OCT in PAH is a promising new prognostic marker of adverse clinical outcome.

Incomplete Shone's complex in the sixth decade of life: echo and cardiac magnetic resonance imaging assessment.

A 51-year-old woman was referred to the Cardiology outpatient clinic for a murmur. She was asympthomatic. Transthoracic echocardiogram showed a parachute mitral valve ( Panel s 1A – C and 2A ), with anomalous and elongated chordae converging into a major papillary muscle (posteromedial) with two heads ( Panel s 1B and 2B , see Supplementary material online, Videos S 1 –S 3 ). Transmitral gradient was normal, and non-significant mitral …

Three-dimensional Tricuspid Area. A New Criterion to Improve Patient Selection for Annuloplasty in Tricuspid Regurgitation

INTRODUCTION AND OBJECTIVES Late functional tricuspid regurgitation after rheumatic left-sided valve surgery is an important predictor of poor prognosis. This study investigated the usefulness and accuracy of 3-dimensional transthoracic echocardiography tricuspid area compared with conventional 2-dimensional diameter (2DD) for assessing significant tricuspid annulus dilatation, providing cutoff values that could be used in clinical practice to improve patient selection for surgery. METHODS We prospectively included 109 patients with rheumatic heart disease in the absence of previous valve replacement. Tricuspid regurgitation was divided into 3 groups: mild, moderate, and severe. Optimal 3-dimensional area (3DA) and 2DD cutoff points for identification of significant tricuspid annulus dilatation were obtained and compared with current guideline thresholds. Predictive factors for 3DA dilatation were also assessed. RESULTS Optimal cutoff points for both absolute and adjusted to body surface area (BSA) tricuspid annulus dilatation were identified (3DA: 10.4 cm2, 6.5 cm2/m2; 2DD: 35 mm, 21 mm/m2); 3DA/BSA had the best diagnostic performance (AUC=0.83). Three-dimensional transthoracic echocardiography tricuspid area helped to reclassify surgical indication in 14% of patients with mild tricuspid regurgitation (95%CI, 1%-15%; P=.03) and 37% with moderate tricuspid regurgitation (95%CI, 22%-37%; P<.0001), whereas 3DA/BSA changed surgery criteria in cases of mild tricuspid regurgitation (17%; 95%CI, 3%-17%; P=.01) compared with 2DD/BSA. On multivariable analysis, right and left atrial volumes and basal right ventricle diameter were independently correlated with 3DA. CONCLUSIONS The current 40 mm threshold underestimates tricuspid annulus dilatation. Although 21 mm/m2 seems to be a reasonable criterion, the combination with 3DA assessment improves patient selection for surgery.