Nicola Galea

Chronic Inhibition of cGMP Phosphodiesterase 5A Improves Diabetic Cardiomyopathy A Randomized, Controlled Clinical Trial Using Magnetic Resonance Imaging With Myocardial Tagging

Background— cGMP phosphodiesterase type 5 protein is upregulated in myocardial hypertrophy. However, it has never been ascertained whether phosphodiesterase type 5 inhibition exerts an antiremodeling effect in nonischemic heart disease in humans. We explored the cardioreparative properties of a selective phosphodiesterase type 5 inhibitor, sildenafil, in a model of diabetic cardiomyopathy. Methods and Results— Fifty-nine diabetic men (60.3±7.4 years) with cardiac magnetic resonance imaging consistent with nonischemic, nonfailing diabetic cardiomyopathy (reduced circumferential strain [&sgr;], −12.6±3.1; increased left ventricular [LV] torsion [&thgr;], 18.4±4.6°; and increased ratio of LV mass to volume, 2.1±0.5 g/mL) were randomized to receive sildenafil or placebo (100 mg/d). At baseline, the metabolic indices were correlated with torsion, strain, N-terminal pro–B-type natriuretic peptide, vascular endothelial growth factor, monocyte chemotactic protein-1, and blood pressure. After 3 months, sildenafil produced a significant improvement compared with placebo in LV torsion (&Dgr;&thgr;: sildenafil, −3.89±3.11° versus placebo, 2.13±2.35°; P<0.001) and strain (&Dgr;&sgr;: sildenafil, −3.30±1.86 versus placebo, 1.22±1.84; P<0.001). Sildenafil-induced improvement of LV contraction was accompanied by consistent changes in chamber geometry and performance, with a 6.5±11 improvement in mass-to-volume ratio over placebo (P=0.021). Monocyte chemotactic protein-1 and transforming growth factor-&bgr; were the only markers affected by active treatment (&Dgr;monocyte chemotactic protein-1: −75.30±159.28 pg/mL, P=0.032; &Dgr;transforming growth factor-&bgr;: 5.26±9.67 ng/mL, P=0.009). No changes were found in endothelial function, afterload, or metabolism. Conclusions— The early features of diabetic cardiomyopathy are LV concentric hypertrophy associated with altered myocardial contraction dynamics. Chronic phosphodiesterase type 5 inhibition, at this stage, has an antiremodeling effect, resulting in improved cardiac kinetics and circulating markers. This effect is independent of any other vasodilatory or endothelial effects and is apparently exerted through a direct intramyocardial action. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00692237.

Right ventricular cardiovascular magnetic resonance imaging: normal anatomy and spectrum of pathological findings

BackgroundThe right ventricle (RV) has been defined as the “forgotten chamber”, as its role in cardiac physiopathology has long been underestimated. Nevertheless, the RV is involved in a wide range of pathological conditions and its altered function may significantly affect the patient’s clinical status.MethodsA selection of the most common cardiovascular magnetic resonance (CMR) features in a spectrum of pathological conditions is illustrated. Although its complex morphology, thin myocardium and trabeculated apex, RV can be accurately imaged by CMR, revealing its involvement in ischaemic and non-ischaemic heart disease. CMR has emerged as the pre-eminent modality in monitoring ventricular performance in congenital heart disease, pulmonary hypertension and cardiomyopathies. Arrhythmogenic right ventricular cardiomyopathy is a difficult diagnosis and the recently revised task force criteria confirmed a crucial role of CMR to increase diagnostic accuracy, by combining detection of RV dilation, regional wall motion and structural abnormalities. Moreover, a multiparametric approach of CMR is often necessary for delineation and characterisation of cardiac masses.ConclusionCMR, combining assessment of morphology, structure and function, has definitively emerged as the reference technique to evaluate a large variety of RV diseases.Teaching Points• CMR offers unique advantages for imaging of many RV congenital, ischaemic and non-ischaemic diseases.• Because of high reproducibility, CMR has a crucial role in decision-making for chronic RV pathology.• The use of CMR increases detection of RV disease as infarction or arrhythmogenic cardiomyopathy.

PDE5 Inhibition Ameliorates Visceral Adiposity Targeting the miR-22/SIRT1 Pathway: Evidence From the CECSID Trial

CONTEXT Visceral adiposity plays a significant role in cardiovascular risk. PDE5 inhibitors (PDE5i) can improve cardiac function and insulin sensitivity in type 2 diabetes patients. OBJECTIVE To investigate whether PDE5i affect visceral adipose tissue (VAT), specifically epicardial fat (epicardial adipose tissue [EAT]), and what mechanism is involved, using microarray-based profiling of pharmacologically modulated microRNA (miRNAs). DESIGN Randomized, double-blind, placebo-controlled study in type 2 diabetes. PATIENTS AND INTERVENTION A total of 59 diabetic patients were randomized to receive 100-mg/d sildenafil or placebo for 12 weeks. Fat biopsies were collected in a subgroup of patients. In a parallel protocol, db/db mice were randomized to 12 weeks of sildenafil or vehicle, and VAT was collected. MAIN OUTCOME AND MEASURES Anthropometric and metabolic parameters, EAT quantification through cardiac magnetic resonance imaging, array of 2005 circulating miRNAs, quantitative PCR, and flow cytometry of VAT. RESULTS Compared with placebo, sildenafil reduced waist circumference (P = .024) and EAT (P = .045). Microarray analysis identified some miRNAs differentially regulated by sildenafil, including down-regulation of miR-22-3p, confirmed by real-time quantitative PCR (P < .001). Sildenafils modulation of miR-22-3p expression was confirmed in vitro in HL1 cardiomyocytes. Up-regulation of SIRT1, a known target of miR-22-3p, was found in both serum and sc fat in sildenafil-treated subjects. Compared with vehicle, 12-week sildenafil treatment down-regulated miR-22-3p and up-regulated Sirtuin1 (SIRT1) gene expression in VAT from db/db mice, shifting adipose tissue cell composition toward a less inflamed profile. CONCLUSIONS Treatment with PDE5i in humans and murine models of diabetes improves VAT, targeting SIRT1 through a modulation of miR-22-3p expression.

Impact of Heart Rate on Myocardial Salvage in Timely Reperfused Patients with ST-Segment Elevation Myocardial Infarction: New Insights from Cardiovascular Magnetic Resonance.

Background Previous studies evaluating the progression of the necrotic wave in relation to heart rate were carried out only in animal models of ST-elevated myocardial infarction (STEMI). Aim of the study was to investigate changes of myocardial salvage in relation to different heart rates at hospital admission in timely reperfused patients with STEMI by using cardiovascular magnetic resonance (CMR). Methods One hundred-eighty-seven patients with STEMI successfully and timely treated with primary coronary angioplasty underwent CMR five days after hospital admission. According to the heart rate at presentation, patients were subcategorized into 5 quintiles: <55 bpm (group I, n = 44), 55–64 bpm (group II, n = 35), 65–74 bpm (group III, n = 35), 75–84 bpm (group IV, n = 37), ≥85 bpm (group V, n = 36). Area at risk, infarct size, microvascular obstruction (MVO) and myocardium salvaged index (MSI) were assessed by CMR using standard sequences. Results Lower heart rates at presentation were associated with a bigger amount of myocardial salvage after reperfusion. MSI progressively decreased as the heart rates increased (0.54 group I, 0.46 group II, 0.38 group III, 0.34 group IV, 0.32 group V, p<0.001). Stepwise multivariable analysis showed heart rate, peak troponin and the presence of MVO were independent predictor of myocardial salvage. No changes related to heart rate were observed in relation to area at risk and infarct size. Conclusions High heart rates registered before performing coronary angioplasty in timely reperfused patients with STEMI are associated with a reduction in salvaged myocardium. In particular, salvaged myocardium significantly reduced when heart rate at presentation is ≥85 bpm.

Novel insights by 4D Flow imaging on aortic flow physiology after valve-sparing root replacement with or without neosinuses

OBJECTIVES This study was undertaken to evaluate the flow dynamics in the aortic root after valve-sparing root replacement with and without neosinuses of Valsalva reconstruction, by exploiting the capability of 4D Flow imaging to measure in vivo blood velocity fields and 3D geometric flow patterns. METHODS Ten patients who underwent valve-sparing root replacement utilizing grafts with neosinuses or straight tube grafts (5 cases each) were evaluated by 4D Flow imaging at a mean of 46.5 months after surgery. We used in-house processing tools to quantify relevant bulk flow variables (flow rate, stroke volume, peak velocity and mean velocity), wall shear stresses and the amount of flow rotation characterizing the region enclosed by the graft and the aortic valve leaflets. RESULTS Despite bulk flows with similar peak velocities, flow rates and stroke volumes (P = 0.31-1.00), the neosinuses graft was associated with a lower mean velocity (P < 0.03) and magnitude of wall shear stress along the axial direction of the vessel wall (P < 0.05) at the proximal root level but remained comparable along the circumferential direction (P = 0.22-1.0) to the straight tube graft. Flow rotation was evidently and systematically higher in the neosinuses grafts, characterized by streamline rotations higher than 270°, nearly triple that of tubular grafts (10.3 ÷ 14.0% of all aortic streamline vs 2.2 ÷ 5.7%, P = 0.008). CONCLUSIONS Recreation of the sinuses of Valsalva during valve-sparing root replacement is associated with significantly lower wall shear stress and organized vortical flows at the level of the sinus that are not evident using the straight tube graft. These findings need confirmation in larger studies and could have important implications in terms of aortic valve durability.

Computed-Tomography and Magnetic Resonance Imaging Assessment of Traumatic Left Anterior Descending Coronary Dissection Causing Acute Myocardial Infarction

![Figure][1] ![Figure][1] [![Graphic][3] ][3] A 16-year-old healthy boy involved in a car accident sustained a blunt chest trauma. He was admitted to the emergency department because of severe chest pain associated with remarkable elevation of the ST-segment in the anterior

Right Ventricular Late Enhancement as a Magnetic Resonance Marker of Glycogen Storage Disease

Glycogen storage disease may affect the heart, particularly as result of a mutation of the LAMP2 and PRKAG2 genes encoding for structural proteins of cardiomyocytes.1 Its recognition and differentiation from hypertrophic cardiomyopathy and other infiltrative and storage diseases may influence treatment and prognosis but are difficult to obtain by conventional noninvasive imaging. A 26-year-old man with family history of sudden cardiac death at a young age (an aunt and grandfather died before 40 years of age) was referred for cardiac magnetic resonance examination because of unexplained increased left ventricular wall thickness at echocardiography (maximal wall thickness, 17 mm) associated with reduced left ventricular function. The ECG (the Figure, A) showed sinus rhythm with increased QRS voltages and abnormalities of ST segment and T wave. Figure. A, A 12-lead ECG showing increased QRS voltages associated …

Right-sided aortic arch with Kommerell’s diverticulum: 64-DCTA with 3D reconstructions

A 75-year-old woman was referred with a long history of dysphagia and wheezing. A chest radiograph revealed the presence of bilateral paratracheal stripes of abnormal appearance (fig 1). Figure 1 Chest radiographs. (A) Posteroanterior view showing abnormal bilateral paratracheal stripes. (B) Lateral view showing a superomedial mediastinal mass displacing the trachea forwards. Computed tomography angiography with 64 detectors (64-DCTA) of …

A feasible and automatic free tool for T1 and ECV mapping

PURPOSE Cardiac magnetic resonance (CMR) is a useful non-invasive tool for characterizing tissues and detecting myocardial fibrosis and edema. Estimation of extracellular volume fraction (ECV) using T1 sequences is emerging as an accurate biomarker in cardiac diseases associated with diffuse fibrosis. In this study, automatic software for T1 and ECV map generation consisting of an executable file was developed and validated using phantom and human data. METHODS T1 mapping was performed in phantoms and 30 subjects (22 patients and 8 healthy subjects) on a 1.5T MR scanner using the modified Look-Locker inversion-recovery (MOLLI) sequence prototype before and 15 min after contrast agent administration. T1 maps were generated using a Fast Nonlinear Least Squares algorithm. Myocardial ECV maps were generated using both pre- and post-contrast T1 image registration and automatic extraction of blood relaxation rates. RESULTS Using our software, pre- and post-contrast T1 maps were obtained in phantoms and healthy subjects resulting in a robust and reliable quantification as compared to reference software. Coregistration of pre- and post-contrast images improved the quality of ECV maps. Mean ECV value in healthy subjects was 24.5%±2.5%. CONCLUSIONS This study demonstrated that it is possible to obtain accurate T1 maps and informative ECV maps using our software. Pixel-wise ECV maps obtained with this automatic software made it possible to visualize and evaluate the extent and severity of ECV alterations.

Ultra low-dose of gadobenate dimeglumine for late gadolinium enhancement (LGE) imaging in acute myocardial infarction: A feasibility study

PURPOSE To assess the feasibility of using an ultra-low dose (0.05 mmol/kg of body weight [BW]) of high relaxivity contrast agent for late gadolinium enhancement (LGE) imaging in patients with acute myocardial infarction (AMI). MATERIALS AND METHODS 17 consecutive patients (mean age, 60.1 ± 10.3 years) with ST-segment elevation AMI underwent two randomized cardiac magnetic resonance studies (exam intervals between 24 and 48h) on a 1.5T unit during the first week after the event using gadobenate dimeglumine (Gd-BOPTA) at the dose of 0.1 mmol/kg BW (standard dose or SD group) and 0.05 mmol/kg BW (half dose or HD group). Image quality was qualitatively assessed. Quantitative analysis of LGE were performed by measuring signal intensity (SI), signal-to-noise ratio (SNR) in the infarcted myocardium (IM), non-infarcted myocardium (N-IM) and left ventricular cavity (LVC) in images acquired at 1, 3, 5, 10, 15 and 20 min after administration of Gd-BOPTA using both contrast media protocol. Contrast-to-noise ratio (CNR) between IM and N-IM (CNR IM/N-IM) and between IM and LVC (CNR IM/LVC) were also quantified for each time point. Moreover the extent of infarcted myocardium was measured. RESULTS 102 LGE images were evaluated for each dose group. Quality score was significantly higher for SD at 1, 15 and 20 min (0.002<p<0.046) and for HD at 5 min (p=0.013). SNR has been higher in the SD group compared to the HD group even though not statistically significant at any time-point for both IM (SD vs. HD: 87.7 ± 73 vs. 65 ± 66; 0.15<p<0.38) and N-IM (SD vs. HD: 22 ± 61 vs. 9.9 ± 6.5; 0.09<p<0.43). LVC SNR was significantly higher with SD at 10 min (p=0.03), 15 min (p=0.001) and 20 min (p=0.004). CNR between the IM and N-IM was significantly higher using SD compared to HD (1382.24 ± 1049 vs. 695.4 ± 500; 0.000<p<0.028) at 10, 15 and 20 min. No significant differences in CNR IM/LVC were noted for HD acquired 5 min after CM administration compared to SD acquired at 10 (p=0.34), 15 (p=0.96) and 20 (p=0.41) min, and between HD at 10 min compared to SD acquired at 15 min (p=0.78) and 20 min (p=0.32). Good correlation between SD and HD (0.56<r(2)<0.85, p<0.024) was found at all time-points in the measuring of IA. CONCLUSION The use of a 0.05 mmol/kg dose of gadobenate dimeglumine is feasible for LGE imaging of acute MI and the best image quality is obtained at 5 min after contrast administration. It could be beneficial in patient with renal failure and a solution to improve the identification of subendocardial infarction reducing examination time, costs and total gadolinium load. However, the standard dose of 0.1 mmol/kg provides overall better image quality, with the best performance obtained at the delay of 10 min or more after Gd-BOPTA administration, and it should be routinely preferred.