To give an update on the emerging role of cardiac magnetic resonance imaging in the evaluation of patients with heart failure with preserved ejection fraction (HFpEF). This is important as the diagnosis of HFpEF remains challenging and cardiac imaging is pivotal in establishing the function of the heart and whether there is evidence of structural heart disease or diastolic dysfunction. Echocardiography is widely available, although the gold standard in quantifying heart function is cardiac magnetic resonance (CMR) imaging.This review includes the recently updated 2016 European Society of Cardiology guidelines on diagnosing HFpEF that define the central role of imaging in identifying patients with HFpEF. Moreover, it includes the pathophysiology in HFpEF, how CMR works, and details current CMR techniques used to assess structural heart disease and diastolic function. Furthermore, it highlights promising research techniques that over the next few years may become more used in identifying these patients.CMR has an emerging role in establishing the diagnosis of HFpEF by measuring the left ventricular ejection fraction (LVEF) and evidence of structural heart disease and diastolic dysfunction. The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging as clinical symptoms and signs are nonspecific . CardiacThe exact pathophysiology of HFpEF remains uncertain and is likely due to diastolic dysfunction, impaired systolic function on exercise, abnormal ventricular-arterial coupling, inflammation and endothelial dysfunction, chronotropic incompetence, altered myocardial energetics and peripheral skeletal muscle metabolism and perfusion, and pulmonary hypertension and renal insufficiency ••. Only Diastole is the time taken for the left ventricle to fill between the closure of the aortic valve and the closure of the mitral valve. During this time, blood flows from the atria to the ventricles due to the pressure difference between the chambers with atrial contraction contributing to the final part of ventricular filling. Diastole is an active, ATP-consuming myocardial process. LV filling and the transmitral pressure gradient are determined by the LV and atrial geometry, loading conditions, viscoelastic properties, pericardial restraint, valve function, heart rate, and temporal synchronization of the atrial and ventricular contraction.Diastolic dysfunction is classified into four phases , Fig. 1.CMR uses a magnetic field, approximately 30,000 times stronger than the earth’s magnetic field, to align the nuclear magnetization of hydrogen atoms that are abundant in the human body. Image contrast is generated by the hydrogen nuclei being intermittently excited by radiofrequency pulses, resulting in longitudinal and transverse relaxation times that are characteristic for different tissues. The CMR sequence details the instructions for the radiofrequency pulses, timed data acquisitions, and magnetic gradient field switches. Spin echo sequences are mainly used for anatomic imaging and tissue characterization, whereas gradient echo sequences are used to acquire moving images. To prevent artifacts from cardiac and respiratory motion, images are gated to the R wave of the electrocardiogram and acquired in end-expiratory breath hold. Intravenous gadolinium chelated contrast agents are used to identify areas of scar or fibrosis, as a lengthened washout indicates reduced functional capillary density in the irreversibly injured myocardium.In assessing a patient with HF symptoms, the LVEF first needs to be calculated. The current techniques to assess diastolic dysfunction include measuring left atrial enlargement (LAE), left ventricular hypertrophy (LVH), mitral inflow pattern, pulmonary vein assessment, LV time volume relations, LV myocardial tagging, flow propagation velocity, and calculating T1/myocardial fibrosis, Fig. 2C × A4C)/L . Recent work in patients with HFpEF has shown that the CMR BAL technique is as accurate as CMR volumetric Simpson’s method, with echocardiography BAL technique less accurate than CMR volumetric assessment particularly with LA dilatation and in patients with atrial fibrillation [Left atrial (LA) size, volume, and wall mass can be accurately measured by CMR, and Simpson’s volumetric method has always been considered the gold standard for measuring atrial volumes . LA voluillation . Howeverillation .The left atrium (LA) has three functions: during ventricular systole, it acts as a reservoir receiving blood from the pulmonary veins and storing energy in the form of pressure; during early diastole, it acts as a conduit for transfer of blood into the left ventricle via a pressure gradient and finally, it has a contractile function, augmenting the LV stroke volume. In patients with normal diastolic function, the relative contribution of the reservoir, conduit, and contractile function of the atria to the LV filling is approximately 40, 35, and 25%, respectively . With ab2 is associated with increased incidence of heart failure independent of age, LV hypertrophy, diabetes, hypertension, myocardial infarction of mitral inflow velocities [Atrial size is known to be prognostic; more than 32 ml/mlocities . Howeverlocities , althouglocities  and LAE locities .The Framingham Study reported that increased left ventricular (LV) mass is associated with a significant excess of cardiovascular mortality and morbidity, independent of hypertension of the presence of coronary artery disease , 18. LefPractically, LVH can be considered as concentric remodeling , concentric hypertrophy , or eccentric remodeling . The accuracy of CMR has been validated ex vivo using post-mortem hearts , 21 and One of the most widely applied techniques in assessing LV diastolic function is the evaluation of the transmitral inflow of pulmonary venous flows using Doppler echocardiography. These results are load-dependent and can change dramatically with only minimal changes in heart rate or preload, and so not evaluate LV relaxation directly.Despite these limitations, phase contrast MRI is an attractive alternative to echocardiographic pulsed wave Doppler as it allows both quantitative assessment of blood velocity and optimal positioning in 3D space of the tomographic plane of interest ensuring accurate alignment and measurements. The acquisition plane is typically perpendicular to the flow direction at the position of the mitral valve at end systole. Data is retrospectively ECG gated and can be acquired either free breathing or with a breath hold. Thirty to 40 cardiac phases are reconstructed resulting in a typical effective temporal resolution of the time velocity curve of 20–30 ms.A time-resolved acquisition with velocity encoding perpendicular to this plane results in a time velocity curve representing one average cardiac cycle. The waveform analysis results in quantification of the early (E) and atrial (A) peak filling velocities, E/A ratio, and deceleration time of the E peak filling velocity. These can be used to classify different grades of diastolic function , 23.When compared to echocardiographic results, the results of phase contrast CMR results correlated 100%, although E and A velocities were found to be systematically lower. However, the CMR acquisition of velocities in a pulsatile flow phantom correlated correctly. These differences in absolute values reflect differences in the nature of acquisition and did not result in any misclassification of diastolic flow abnormalities between modalities ; echo daOne challenge in CMR, however, is that the acquisition plane remains fixed during the cardiac cycle and does not move with the cyclical motion of the mitral annulus. Acquisition techniques have been introduced using moving slice velocity mapping  and threPhase contrast MRI can also assess pulmonary veins. Rathi et al. found that only 68% of echo cases were able to assess the pulmonary veins, compared to 100% with CMR . The bloThe LV time-volume relation is recorded from a series of breath-held time-resolved parallel short-axis planes or a radial stack of long-axis planes. Segmenting and summating the endocardial borders results in the end-diastolic and end-systolic LV volumes. The stroke volume and systolic function can be calculated from the difference between the end-diastolic and end-systolic volumes. Early peak filling rate, time to peak filling rate, and atrial filling fraction can also be calculated from this information. Diastolic dysfunction is associated with decreased peak filling rates and increased time to peak filling rates. Despite improvements in the definition of endocardial borders and the use of automated segmentation , the accIt is possible to label or “tag” myocardium by selective saturation pulses in specific regions in planes perpendicular to the imaging plane, Fig. Edvardsen et al. demonstrated an association with regional diastolic dysfunction in 218 asymptomatic patients with left ventricular hypertrophy who had no evidence of clinical cardiovascular disease or LV dysfunction . More reThe flow propagation velocity (Vp) is a measure of the LV suction force that has been attributed to LV relaxation. In addition to diastolic function, variables such as flow field, viscoelastic properties, inertial force, LV geometry, systolic function, mitral valve function, and LV contractile function influence intraventricular flow. A Vp > 50 cm/s in echocardiography is considered to be normal. Attempts with three-dimensional three-directional velocity encoding CMR may provide quantitative information on the intraventricular blood flow field, although long acquisition times may limit the universal uptake of this technique .Myocardial fibrosis is a pathological increase in the myocardial collagen content caused by increased collagen synthesis in the interstitium  or myocyte replacement (resulting in scarring) . Increasr = 0.51~0.81) [Diffuse interstitial fibrosis, a precursor for replacement fibrosis, is not detected by late gadolinium enhancement but correlates with T1 mapping, which allows a quantitative assessment of diffuse cardiac fibrosis and estimations of the extracellular matrix volume (ECV) –41. Stud51~0.81) .T1 mapping reflected diffuse fibrosis in 25 heart failure patients (LV ejection fraction 35 +/− 3.3%) . In 2014Despite recent development in these techniques and the introduction of updated ESC diagnostic guidelines, no one assessment is definitive in detecting patients with HFpEF. Recent research in pulse wave velocity, MR elastography, and 4D flow assessment looks promising in these patients.It has been hypothesized that magnetic resonance elastography (MRE) may act as a biomarker for patients with HFpEF as it uses mechanical shear waves to quantitatively assess the stiffness of tissues. Applying stress to a material results in a strain response of that tissue which can be measured. When the material is subjected to periodic shear, shear waves occur. The pair of equal forces acting in opposite directions along the two faces of the layer causes a change of shape, even though the volume remains unchanged. If the medium is elastic, then the layer will resume its original shape after the shear wave has passed. A wave is propagated as the adjacent layers undergo transient shear with equal forces acting in opposite directions, and then resume their original shape. MR elastography has been shown to map the shear stiffness of soft tissues . In 20173D phase contrast MRI, known as 4D CMR, allows volumetric flow imaging in a single acquisition. Complex blood flow patterns can be intuitively visualized as they unfold in multiple dimensions over time. Diastolic dysfunction is associated with abnormal intracardiac blood flow and it is possible to analyze quantitatively with 4D flow. This analysis can identify and monitor diastolic dysfunction. Blood transiting the left ventricle can be divided into four separate functional components: direct flow which enters and exits a single heartbeat, retained inflow which enters but does not exit, delayed ejection flow which exits on the subsequent heartbeat, and the residual volume that resides in the ventricle for at least two cardiac cycles. Investigation of these relative percentages of flow components and the kinetic energy and momentum will allow a refined analysis of the dynamic of ventricular filling and ejection. 4D flow can uniquely identify flow differences not seen with conventional hemodynamic assessment. Diminished direct flow and reduced kinetic energy of the direct flow at end diastole can be identified. As a consequence, increased workload is placed on the left ventricle to eject the same stroke volume.There is no doubt that CMR offers excellent spatial resolution and is the gold standard for assessment of LV volumes and myocardial tissue characterization. However, not all departments have access to CMR imaging and the scanners are more expensive that transthoracic echocardiography, as well as taking longer. Furthermore, patient selection is critical as some patients cannot tolerate the scan due to claustrophobia  and patients with certain implants are not allowed in the scanner. There is a small risk of anaphylaxis due to contrast, and patients with renal impairment need reduced doses with contrast administration being contraindicated if the GFR < 15 mls/min.Cardiac MRI is fundamental in the assessment and characterization in heart failure patients. Despite challenges with long acquisition times and challenges in post-processing, CMR has a pivotal role in measuring LV systolic function and identifying left atrial enlargement and left ventricular hypertrophy, as well as other measures of diastolic function.


The electrocardiogram (ECG) is the most widely used screening tool to detect left ventricular hypertrophy (LVH). However, current diagnostic criteria are highly insensitive, particularly in modern society with increasing prevalence of obesity. We aimed to use cardiac magnetic resonance (CMR) imaging to assess anatomical LV axis  and LV mass across a wide range of different body sizes, to generate a simple and clinically applicable adjustment factor that could be applied to increase the sensitivity of the most commonly used diagnostic criteria.2) underwent CMR evaluation (1.5T) to determine anatomical LV axis and LV mass, as well as a standard 12-lead surface ECG. The anatomical LV axis was defined as the plane between the centre of the mitral valve and the LV apex using multi-planar reconstruction of thoracic Half fourier Acquisition Single shot Turbo spin Echo (HASTE) images within cmr42 ©. LVH was defined as >2SD higher than the mean of the normal Oxfordshire population from which the study sample was taken . The effect of BMI and LV axis on Sokolow-Lyon index (S in V1 + R in V5/V6 ≥ 35 mm) and Cornell criteria (S in V3 + R in aVL >28 mm (♂) or > 20 mm (♀)) were then calculated and an adjustment factor generated. A second validation cohort  underwent CMR evaluation (1.5T) to determine LV mass, and standard 12-lead surface ECG. Sensitivity and specificity for the ECG detection of CMR derived LVH was then determined for the study groups with and without adjustment.A single centre, retrospective study of 1295 participants. An initial cohort  with a wide range of body mass index  dramatically improves the diagnostic accuracy for detecting LVH. As the ECG, worldwide, remains the most widely used screening tool for LVH, implementing these findings should translate into significant clinical benefit.


To determine if patients with Cardiac syndrome X (CSX) have decreased global myocardial perfusion during adenosine stress as assessed by cardiovascular magnetic resonance (CMR) compared to healthy controls.Thirteen CSX patients , here defined as a history of chest pain and pathological ECG reaction during stress (> 1 mm ST-depression at stress or after 4 minutes of recovery) but normal myocardial perfusion assessed by myocardial perfusion scintigraphy (SPECT), were included. In addition, 15 positive controls  with stress-induced perfusion defects by SPECT, and 18 healthy controls  were also included. All subjects underwent quantitative flow measurement in the coronary sinus by CMR at rest and during adenosine stress. Coronary sinus flow (ml/min) was normalized to LVM enabling quantification of global myocardial perfusion (ml/min/g). All patients underwent first-pass perfusion at rest and during adenosine stress and presence of myocardial fibrosis/infarction was assessed by late gadolinium enhancement (LGE).CSX patients showed significantly lower global myocardial perfusion during adenosine stress compared to healthy controls . There was, however, no significant difference between CSX patients and positive controls . Female controls showed significantly higher global myocardial perfusion compared to male controls . Furthermore, female CSX patients (N=9) showed significantly lower global myocardial perfusion during adenosine stress compared to female controls . The same trend was seen for male CSX patients (N=4) compared to male controls, . No CSX patient showed myocardial fibrosis/infarction on LGE. All patients except one had normal findings on first-pass perfusion, who showed a mild regional subendocardial perfusion deficit in the inferior part of the midventricular septum.Patients with CSX, defined as history of chest discomfort and pathological stress ECG but normal regional myocardial perfusion by SPECT, have decreased global myocardial perfusion compared to healthy controls as assessed by CMR. Furthermore, there seems to be a gender difference in global myocardial perfusion. These findings indicate that CSX patients may have impaired myocardial microvascular circulation.


This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential  and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.Non-uniform shortening of the action potential duration (APD For instance, the DIAMOND clinical trial has raised serious concerns regarding torsadogenic effects produced by dofetilide, class III antiarrhythmic agent, in patients with congestive heart failure [+ channel blocker, in patients with healed myocardial infarction [In susceptible patients, antiarrhythmic drug therapies can paradoxically precipitate malignant ventricular tachyarrhythmia, torsade de pointes, thereby increasing mortality rates . The pro failure . In the farction . An incrfarction –5.Drug-induced cardiac electrical instability often develops unexpectedly, and its early detection is difficult due to the limited prognostic value of the existing arrhythmic biomarkers. Recently, the electrical restitution analysis has been proposed as a novel approach for evaluation of the drug safety profile –7. When Although drug-induced arrhythmia was partly attributed to the steepening of the electrical restitution in some studies –12, the With these considerations in mind, the present study examined effects of four pharmacological agents with clinically proved arrhythmogenic effects  on the spatial heterogeneities in APD restitution and the JTpeak vs. JTend difference in the restitution slope, in isolated, perfused guinea-pig hearts.This study complies with the European Community Guidelines for the Care and Use of Experimental Animals, and was approved by the Animal Ethics Screening Committee of the Panum Institute (clearance number: 2010/561-1799).2 and 5%CO2. The perfusion solution contained (in mM) 118.0 NaCl; 4.7 KCl; 2.5 CaCl2; 25 NaHCO3; 1.2 KH2PO4; 1.2 MgSO4; and 10.0 glucose, and had a pH of 7.4. The aortic perfusion pressure (65–70 mm Hg) was measured with a ISOTEC pressure transducer and the coronary flow rate was determined using an ultrasonic flowmeter probe  placed just above the aortic cannula. The electrical activity of the heart preparations was assessed from the volume-conducted ECG as well as monophasic action potential recordings. Throughout the experiments, the heart preparations were kept immersed in the temperature-controlled, perfusate-filled chamber to minimize thermal loss. Aortic pressure, coronary flow rate, ECG and monophasic action potentials were continuously monitored using the 16-channel PowerLab system .The heart preparations were obtained from female Dunkin-Hartley guinea-pigs, assuming that females have reduced cardiac repolarization reserve and therefore more susceptible to drug-induced proarrhythmia, as compared to males . The exp90). Electrical stimulations were applied at LV epicardium close to the adjacent MAP recording electrode using 2 ms rectangular pulses of twice diastolic threshold current generated by a programmable stimulator . LV pacing thresholds were measured both at baseline and upon drug infusion, and the stimulating current strength was adjusted appropriately whenever necessary.In order to slow the intrinsic beating rate and enable ventricular pacing over a wide range of diastolic intervals, both atria were removed and the atrioventricular (AV) node was crushed mechanically with forceps prior to taking electrophysiological recordings. Monophasic action potentials (MAP) were obtained from the endocardial and the opposite epicardial recording sites at the base of the left ventricular (LV) lateral wall, and from the right ventricular (RV) epicardial base  to the peak of the T wave , and to the end of the T wave  , panel B1-S1 pacing interval in successive stimulations. The measurements were started with a S1-S1 cycle length of 550 ms , which was then reduced to 500 ms, followed by further reductions in steps of 20 ms over an S1-S1 range from 500 to 200 ms, and by 5–10 ms reductions from 200 ms down to the pacing intervals (about 170 ms) producing 2:1 conduction block. In AV-blocked preparations, the minimum pacing intervals achieved with this protocol remain significantly greater than the threshold value of S1-S1 interval for inducing repolarization alternans (90–100 ms in intact guinea-pig heart) [The electrical restitution kinetics was assessed using the steady-state pacing protocol –12. In bg heart) , meaning1-S1 cycle length and the measured APD90 (APD90 restitution) or JTpeak and JTend interval (JT restitution) values. The electrical restitution was analysed by plotting APD90 and JT intervals as a function of the preceding DI. The restitution curves were fitted using double-exponential function: y = y0 + A1exp(-DI/τ1) + A2exp(-DI/τ2), where y represents APD90 or JT interval value, y0 is a free-fitting variable, A1 and A2 are the amplitudes, and τ1 and τ2 are the time constants of the fast (A1 and τ1) and slow (A2 and τ2) exponential components obtained by a least squares fit. The curve fitting was performed using Igor Pro 6.0 software .Once the electrical stimulations were completed, appropriate diastolic intervals (DI) were calculated as a difference between the S90 restitution kinetics was assessed by calculating the difference between the maximum restitution slopes measured at LV endocardium vs. LV epicardium, and those measured at RV epicardium vs. LV epicardium. With ECG recordings, the difference between the maximum slopes obtained from JTend vs. JTpeak restitution curves was taken as an ECG estimate of the regional ventricular heterogeneities in electrical restitution.The obtained exponential curves were differentiated to determine the maximum restitution slope value . For precise dosing, drug infusions were performed at a rate of 0.3 ml/min using a calibrated infusion pump, while perfusing the hearts with protein-free saline solution at a constant coronary flow rate (see above). Dofetilide (10 nM), quinidine (5 μM), procainamide (10 μM), and flecainide (1.5 μM)  were infused over 30 min, at concentrations close to the maximum free (i.e. protein-unbound) therapeutic plasma levels –25 S1 T.P values less than 0.05 were considered to be significant.Data are expressed as mean ± standard error of the mean. One-way ANOVA was used for multiple comparisons, and paired t-tests were used to compare two data sets. 90 (panels D and E) and JT intervals (panels F and G) obtained prior to drug infusion in heart preparations from all experimental groups. Over a range of variable diastolic intervals, action potential duration was found to be 5–10 ms shorter at LV epicardium compared to the corresponding LV endocardial or RV epicardial APD90 values  provoked an exponential reduction of both ventricular APD90 and JT intervals, whereby the steepness of the electrical restitution curves was progressively increasing upon a reduction of the diastolic interval  and RV epicardium (0.69±0.03) compared to the slope determined at LV epicardium (0.57±0.02) (P = 0.0001), indicating the presence of spatial heterogeneities in electrical restitution, both over LV transmural and RV-to-LV transepicardial planes. With ECG recordings, the maximum restitution slope was greater for JTend interval (0.91±0.05) compared to JTpeak interval (0.58±0.02) (P<0.0001), thus providing an ECG correlate for assessments of the regional non-uniformities in electrical restitution.0 values , panel D0 values , panel F90-to-DI relations assessed at different ventricular regions. Dofetilide significantly prolonged repolarization at LV endocardium, LV epicardium, and RV epicardium, thus causing the APD90 restitution curves to shift upwards (90 by dofetilide was markedly accentuated at the long (above 250 ms) as compared to the short (less than 100 ms) diastolic intervals, which contributed to the steepening of the restitution curve, as evidenced by increased maximum slope values, at each ventricular recording site , while increasing APD90 from 140±3 ms to 146±4 ms at the minimum DI (~50 ms). The difference in APD90 lengthening produced by dofetilide at the maximum DI vs. the minimum DI (27 ms vs. 6 ms) therefore amounted 21±2 ms. At LV epicardium (90 lengthening determined at the maximum DI vs. the minimum DI (22 ms vs. 14 ms) was found to be only 8±1 ms, whereas at RV epicardium  compared to LV epicardium (from 0.51±0.05 to 0.65±0.06) (90 restitution slope determined at baseline was further amplified by dofetilide (90 restitution curve by dofetilide was produced at RV epicardium (the maximum slope increased from 0.69±0.06 to 0.96±0.09) compared to LV epicardium  and RV epicardium (11±1 ms) compared to that determined at LV epicardium (8±1 ms). With procainamide  at the maximum DI, and by 19 ms (from 131±2 ms to 150±3 ms) at the minimum DI. At RV epicardium  and RV epicardium   was more prominent than that produced at the maximum DI . This resulted in flattening of the restitution curve obtained at LV epicardium (P = 0.01). No change in the maximum restitution slope determined at LV endocardium and RV epicardium, in association with the reduced slope value at LV epicardium, translated to the increased spatial heterogeneities in electrical restitution upon flecainide administration, both over LV transmural and RV-to-LV epicardial planes  , panel Bicardium , panel EP = 0.01) by flecainide. No change in JTend restitution kinetics, in association with reduced JTpeak restitution slope, resulted in amplified JTend vs. JTpeak difference in the maximum restitution slope value . Second, the study demonstrates that an increase in regional APD90 restitution heterogeneities translates to the increased JTpeak vs. JTend difference in the maximum restitution slopes determined from ECG recordings at variable pacing rates.The main findings from the present study are twofold. First, it is shown that LV transmural and RV-to-LV epicardial dispersion of the maximum APDIKr and IKs , and to the increased intracellular Na+ and Ca2+ concentrations at rapid cardiac activation rates [+-Ca2+ exchanger and Na+-K+ pump, and through the Ca2+-induced inactivation of ICa in cardiac myocytes.Electrical restitution refers to the rate-dependent shortening of ventricular repolarization, which is attributed to incomplete deactivation of on rates –27. The 2+ transient alternans in cardiac myocytes [A steep slope of APD rate adaptation has been shown to facilitate ventricular fibrillation by inducing APD and Camyocytes –7, 28. Tmyocytes –30. Likemyocytes , 31. TheOwing to the spatial heterogeneities in expression and function of repolarizing ionic currents , the amo+ currents that govern phase-3 repolarization. In guinea-pig heart, the density of IK, the delayed rectifier, is significantly less in endocardial than epicardial myocytes [IK1 current (the inward rectifier) is smaller in RV than LV myocytes [IK (IKs) is reduced to a greater extent than the rapid component (IKr), in endocardium vs. epicardium [IKr-to-IKs ratio in endocardial cells. In connection with this, the simulations that utilize the guinea-pig ventricular cell model suggest that a larger IKr-to-IKs ratio contributes to the faster rate of APD changes at short diastolic intervals [The present study reports on significant regional restitution heterogeneities in guinea-pig heart, wherein the maximum slope of APD restitution is greater at the endocardium vs. the epicardium, and in the RV vs. the LV chamber  vs. those with the latest (JTend) repolarization times. As such, the JTpeak vs. JTend restitution slope difference is more integrative metric than the Tpeak-to-Tend interval in assessments of repolarization dynamics. This difference can be particularly important in predicting arrhythmia provoked by an abrupt increase in cardiac activation rate. Notably, in the clinical setting, ambulatory ECG monitoring in victims of sudden death suggests that fatal cardiac arrest is often preceded by transient heart rate acceleration –65. In t+ currents that govern cardiac repolarization should be taken into account when considering the practical aspects of this study. In human ventricular myocytes, phase-3 repolarization is mostly controlled by IKr, whereas in guinea-pig it is primarily determined by IKs [Ito, the transient outward K+ current, which contributes to phase-1 repolarization in the human ventricular action potential, is not expressed in guinea-pig myocytes [Species-related differences in the outward Kd by IKs –67. Likemyocytes . Neverthmyocytes –36, and myocytes , 37 are INa blockers such as flecainide, quinidine, and procainamide, another important proarrhythmic determinant to consider is the restitution of conduction velocity, which determines the excitation wavelength dynamics [+ channel blockers effects on the restitution of the excitation wavelength.This study explored changes in the rate adaptation of ventricular repolarization upon infusion of arrhythmogenic drugs, with particular focus on APD and JT restitution kinetics. With dynamics . Althougdynamics , which h90 restitution slope in perfused guinea-pig heart, and the JTpeak vs. JTend difference in the restitution slope value determined from ECG, are increased by drugs with arrhythmogenic profiles, such as dofetilide, quinidine, procainamide, and flecainide.Local heterogeneities in distribution of the maximum APDS1 Table(DOC)Click here for additional data file.


The formation of the ventricles of the heart involves numerous carefully regulated temporal events, including the initial specification and deployment of ventricular progenitors, subsequent growth and maturation of the ventricles through “ballooning” of chamber myocardium, the emergence of trabeculations, the generation of the compact myocardium, and the formation of the interventricular septum. Several genes have been identified through studies on mouse knockout and transgenic models, which have contributed to our understanding of the molecular events governing these developmental processes. Interpretation of these studies highlights the fact that even the smallest perturbation at any stage of ventricular development may lead to cardiac malformations that result in either early embryonic mortality or a manifestation of congenital heart disease.


Type 2 diabetes mellitus (T2DM) is a multi factorial disease, affecting clinical outcomes in failing heart patients treated by cardiac resynchronization therapy with a defibrillator (CRT-d).One hundred and ninety-five T2DM patients received a CRT-d treatment. Randomly the study population received a CRT-d via multipolar left ventricle (LV) lead pacing , vs a CRT-d via bipolar LV pacing . These patients were followed by clinical, and instrumental assessment, and telemetric device control at follow up. In this study we evaluated, in a population of failing heart T2DM patients, cardiac deaths, all cause deaths, arrhythmic events, CRT-d responders rate, hospitalizations for HF worsening, phrenic nerve stimulation (PNS), and LV catheter dislodgment events (and re-intervention for LV catheter re-positioning), comparing multipolar CRT-d vs bipolar CRT-d group of patients at follow up.At follow up there was a statistical significant difference about atrial arrhythmic events , hospitalizations for HF worsening , LV catheter dislodgments , PNS , and LV re-positioning , comparing multipolar CRT-d vs bipolar CRT-d group of patients. Multipolar pacing was an independent predictor of all these events.CRT-d pacing via multipolar LV lead vs bipolar LV lead may reduce arrhythmic burden, hospitalization rate, PNS, LV catheters dislodgments, and re-interventions in T2DM failing heart patients.Clinical trial number NCT03095196 Type 2 diabetes mellitus (T2DM) is a worldwide increasing disease . T2DM mascreening phase) with stable chronic heart failure, New York Heart Association (NYHA) functional class II or III, left bundle branch block, severe left ventricle ejection fraction reduction (LVEF < 35%), stable sinus rhythm, candidates to receive a CRT-d treatment according to the international guidelines   vs n 9 (9.4%), p value 0.018], as compared to bipolar LV pacing   vs 24 (25%), p value 0.046], comparing multipolar pacing vs bipolar pacing (Table In our study the multipolar CRT-d pacing was found to be superior to the bipolar CRT-d pacing respect to the reduction of PNS events, LV leads dislodgment, re-interventions for LV leads dislodgments, hospitalizations for HF worsening, and AF events Figs. ; Table 37] Table a. PNS isng Table b, c. In vs n 9 9.%, p valuvs n 9 9.%, p valuvs n 9 9.%, p valuvs n 9 9.%, p valuThis study had few limitations. As first, we examined a small percentage of T2DM failing heart patients treated by multipolar vs bipolar CRT-d, as compared to overall population. This was due to loss of patients during follow up, and to the low adherence of patients to the study protocol as discussed in results session. Second, this study was conducted at 12 months follow up time, and this short time follow up duration may affect the long term follow up prognosis, and primary and secondary clinical outcomes. Third, we have to report the paucity of clinical characteristics that would provide a more accurate comparison to clinical trial subjects. At last we have not investigated the molecular, and epigenetic aspects induced by T2DM in failing heart patients, and/or modulated by CRT-d. In fact, T2DM by an altered glucose homeostasis may induce electrophysiological changes, which leads to QRS prolongation, decreased conduction velocity and increased arrhythmogenesis, and this may condition clinical prognosis . We mentIn T2DM failing heart patients multipolar CRT-d pacing may reduce PNS, catheters dislodgments, and re-interventions as compared to bipolar CRT-d pacing. This effect may be associated to reduction of AF events, and hospitalizations for HF worsening. Multipolar CRT-d pacing may offer a relevant hemodynamic advantage over a fixed conventional CRT-d pacing by a single site LV lead in failing heart patients , 44. In


PAH) are often due to right ventricular (RV) failure and associated left ventricular (LV) dysfunction. We investigated regional myocardial remodeling and function as the basis for adverse ventricular‐ventricular interactions in experimental chronic RV pressure overload. Two distinct animal models were studied: A rabbit model of increased RV pressure‐load through progressive pulmonary artery banding A rat model of monocrotaline (MCT)‐induced pulmonary arterial hypertension (PAH). Regional myocardial function was assessed by speckle‐tracking strain echocardiography and ventricular pressures measured by catheterization before termination. Regional RV and LV myocardium was analyzed for collagen content, apoptosis and pro‐fibrotic signaling gene and protein expression. Although the RV developed more fibrosis than the LV; in both models the LV was substantially affected. In both ventricles, particularly the LV, fibrosis developed predominantly at the septal hinge‐point regions in association with decreased regional and global circumferential strain, reduced global RV and LV function and up‐regulation of regional transforming growth factor‐β1 (TGFβ1) and apoptosis signaling. A group of PAH rats who received the TGFβ blocker SB431542 showed improved RV function and reduced regional hinge‐point myocardial fibrosis. RV pressure‐loading and PAH lead to biventricular TGFβ1 signaling, fibrosis and apoptosis, predominantly at the septal hinge‐point regions, in association with regional myocardial dysfunction. This suggests that altered geometry and wall stress lead to adverse RV‐LV interactions through the septal hinge‐points to induce LV fibrosis and dysfunction.Death and morbidity in pulmonary arterial hypertension ( RV pressure‐load from pulmonary arterial hypertension (PAH) or pulmonary outflow obstruction carries high morbidity and mortality –connective tissue growth factor  signaling  in which the pulmonary artery banding (PAB) device was left un‐inflated, and (2) PAB‐group (n = 14) with stepwise PAB inflation over 2‐weeks (to avoid acute RV failure), aiming for systemic RV pressures after the third inflation. PAB inflation was monitored by echocardiography for PAB gradient, septal curvature and RV systolic pressure by tricuspid regurgitation Doppler.Twenty 6‐week‐old male New Zealand White rabbits had an adjustable vascular cuff  placed around the main pulmonary artery through a left thoracotomy  received a single subcutaneous injection of 0.9% saline (B) PAH rats (n = 14) received a single subcutaneous injection of 60 mg/kg monocrotaline to induce severe PAH. (C) To further assess the role of TGFβ signaling in inducing regional LV myocardial remodeling a 3rd group of rats (n = 6) received the TGFβ blocker SB431542 (500 nmol/kg/day by subcutaneous injection). SB431542 was administered from 2‐weeks after the monocrotaline injection, for a duration of 3‐weeks, until the terminal experiment. Four‐weeks after saline or monocrotaline injection, animals were examined with echocardiography and a high‐fidelity micromanometer catheter while anesthetized with 3% isoflurane. Thereafter, animals were sacrificed by cardiectomy during deep anesthesia and tissues harvested for regional histological and molecular investigations.Nineteen 6‐week‐old male Sprague–Dawley rats  weighing approximately 200 g at protocol onset were divided into the following groups: (A) sham‐controls , and performed in accordance with the Guiding Principles in the Care and Use of Animals of the American Physiologic Society.Transthoracic echocardiography was performed with a Vivid 7 or E9 system  using a 12‐MHz phased array probe during 3% isoflurane anesthesia. Maximum frame rates were 275 frame/second. The myocardial performance index (MPI) was used as a measure of global RV and LV systolic and diastolic function , the RV and LV endocardial border were traced from an end‐systolic frame to include the free‐wall and septum. The region of interest was manually adjusted to the wall thickness. Adequate tracking was visually verified and the region of interest corrected as necessary.Hemodynamic measurements and echocardiography were done on the day of the terminal experiment. Systolic and diastolic RV and LV pressures were measured using a 3F high‐fidelity pressure‐tipped catheter. For analog digital converter we used CD Leycom Sigma 5/DF  for volumes and Millar PCU‐2000  for pressures. The software used was Notocord version 4.2 .To assess the regional nature of myocardial remodeling and fibrosis, RV and LV myocardium was sampled from the RV free‐wall, LV free‐wall, septum and RV and LV septal hinge‐point regions as shown in Figure μm stained sections from transverse sections of the entire heart by automated planimetry . Analyses were performed blinded to experimental group.Fibrosis was assessed as the collagen content; calculated as the regional cardiac collagen volume fraction , as quantified by picrosirius red F3BA (PSR) 5 α and β myocyte heavy chain (MHC) protein were analyzed as markers of failing myocardium in response to pressure‐loading , SMAD3, pSMAD3, matrix metalloproteinases‐2 and ‐9 and endothelin‐receptors‐A and B were analyzed as key molecular markers of fibrosis and extra‐cellular matrix remodeling Leask . α and βμg) was loaded onto each lane of an 8% to 16% Tris‐Glycin gel (Helixx). Proteins were separated by electrophoresis and transferred to a nitrocellulose membrane using an electro‐blotting apparatus . Membranes were incubated with 5% Bovine Serum Albumin (BSA) for 1 h to decrease nonspecific binding. Samples were then incubated with the following primary antibodies overnight at 4°C: Connective Tissue Growth Factor (CTGF) , SMAD3 and 4 , pSMAD3  Endothelin‐1 , and matrix metalloproteinases 2 (MMP‐2) . Caspase 3 and 8 , α and β MHC  samples were washed and incubated with peroxidase – conjugated secondary antibody, and detected using the Amersham ECL  detection kit. Glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) was used as the internal standard.Cardiac tissues samples were homogenized with lysis buffer and diluted 1:1 with 2 × SDS sample buffer . An equal amount of protein . Real‐time PCR was performed as follows: 10 min at 95°C, 40 cycles of 95°C for 15 sec, followed by 60°C for 1 min. GAPDH was used as internal standard. Primer sequences are listed in Table 1 of Appendix Ct) were provided by the software, and the 2−ΔΔCt method of relative quantification utilized to compute relative expression levels.Cardiac pro‐fibrotic gene expression levels were measured by the StepOnePlus™ real‐time PCR system  using Power SYBRP‐value of less than 0.05 was considered statistically significant. Interclass correlation was assessed by the two‐way random effects‐model using .Grouped data are presented as mean ± standard deviation (SD). Groups (rabbits) were compared using the non‐parametric Mann–Whitney test . In both models, LV, collagen content was higher at the septal hinge‐point regions versus shams  was up‐regulated in the RV and LV free‐walls and septal hinge‐point regions compared to shams  and LV (caspase‐3) septal hinge‐point regions in PAB rabbits versus shams Fig. A–C. The ams Fig. A–C.β1 signaling 4. Regional fibrosis is associated with regional myocardial dysfunction and global biventricular dysfunction.Although adverse ventricular‐ventricular interactions leading to LV injury and dysfunction are increasingly recognized as important predictors of poor outcomes in RV pressure loading and PAH, the underlying mechanisms remain inadequately defined  and analysis of molecular signaling. The results of cardiac function obtained by echocardiography correlated with these outcomes.β1 fibrosis signaling to drive adverse ventricular‐ventricular interactions, which are emerging as an important risk factor for mortality in PAH.In conclusion, RV pressure loading and PAH lead to extensive RV and LV fibrosis and apoptosis in association with up‐regulation of molecular fibrosis signaling most prominently at the RV and LV septal hinge‐points in association with decreased myocardial function in these regions. Taken together, our findings suggest that geometrical changes and/or RV‐LV interactions at the septal hinge‐points up‐regulate TGFEAN received financial support for her stay at The Hospital for Sick Children from the Bonnelykke foundation and the travel fund at Aarhus University. None of the authors have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.Appendix S1. Supplement data Western blot and rtPCR.Click here for additional data file.


Amyloidosis is a disease caused by deposits of insoluble fibrils inextracellular spaces. The most common type of familial amyloidosis ismediated by mutation of transthyretin, especially Val30Met. Symptoms andejection fraction decrease may occur in cardiac amyloidosis only in case ofpoor prognosis. Myocardial strain detected by two-dimensional speckletracking echocardiography can indicate changes in myocardial function atearly stages of the disease.To determine the accuracy of left ventricular longitudinal strain bytwo-dimensional speckle tracking echocardiography in patients with familialamyloidosis caused by Val30Met transthyretin mutation.Eighteen consecutive patients, carriers of transthyretin mutation, wereevaluated by two-dimensional speckle tracking echocardiography, by whichmyocardial strain curves were obtained, following the American Society ofEchocardiography recommendations.Patients were divided into three groups: 1- Val30Met with cardiacamyloidosis; 2-Val30Met with extracardiac amyloidosis; 3 - Val30Met withoutevidence of disease. As the three groups were compared by the Mann-Whitneytest, we found a statistically significant difference between groups 1 and 2in the mean longitudinal tension (p=0.01), mean basal longitudinal strain(p=0.014); in mean longitudinal tension and mean longitudinal strain betweengroups 1 and 3 (p=0.005); and in the ratio of longitudinal strain of apicalseptum segment to longitudinal strain of basal septum (p=0.041) betweengroups 2 and 3.Left ventricular longitudinal strain detected by two-dimensional speckletracking echocardiography is able to diagnose left ventricular dysfunctionin early stages of familial amyloidosis caused by transthyretin Val30Metmutation. The main clinical manifestations of cardiacamyloidosis (CA) are: restrictive heart disease, systolic dysfunction, posturalhypotension and conduction disturbances. Rapezzi et al. reported a 98% survivalafter two years of TTR CA.4Amyloidosis is a rare disease caused by deposits of proteins in the extracellularspace of organs and tissues. The familial forms of the disease are commonlyassociated with mutations of genes related to proteins. The most frequent istransthyretin (TTR), a protein that is synthesized in the liver, choroid plexus andretina, and that acts in the transport of thyroxine (T4) and retinol-binding proteinin the blood.5  wall, hypokinesia, right ventricularfree wall thickening, atrial septal thickening, valve thickening or valve failure,atrial dilatation and pericardial effusion5 . TwodimThis is a cross-sectional, descriptive, comparative study on CA patients and geneticcarriers of Val30Met mutation, and individuals without the mutation and withoutcardiovascular diseases as controls. Twenty-eight patients were selected andassessed from February 2014 to March 2015. Patients were divided into four groups -patients with familial CA with Val30Met mutation (n=6); patients with Val30Metmutation with diagnosis of familial extracardiac amyloidosis confirmed by biopsy(n=4); patients with Val30Met without amyloidosis (n=4); and a control group(n=14).Patients were enrolled in the outpatient neurology service of Antonio PedroUniversity Hospital and in private offices of neurology run by professors of thishospital, and by contact to the Brazilian Association of Paramyloidosis byinternet.Sample calculation was based on the following assumptions:15selected 26 patients with TTR. We took this number as a reference for our samplecalculation.In a similar study, Phelan et al.The expected margin of error is 5%, with 95% confidence error. The distribution of CAin this population is unknown; however, we extrapolated the value of 50% of primaryamyloidosis (AL) distribution, and used it as reference for our samplecalculation.http://www.raosoft.com/samplesize.html, and the sample sizecalculated was 26.We used the online sample calculator available at Age > 18 years.Agreement to participate and signature of the informed consent formPatients carriers of TTR genetic mutation and/or with diagnosis of TTRamyloidosis (ATTR).Poor quality of two-dimensional echocardiogram, established as thepresence of artifacts or poor visualization of more than two cardiacsegments.Tachycardia (heart rate over 100 bpm).Atrial fibrillation or other arrhythmias with variation in the R-Rinterval.Other causes of ventricular hypertrophy - systemic arterialhypertension (SAH), hypertrophic cardiomyopathy (HCM), aorticstenosis, Fabry disease.Patients attended a medical visit, during which their demographic data werecollected, and anamnesis and physical exam were conducted. Electrocardiography(ECG), conventional echocardiography (echo) and two-dimensional STE wereperformed.17The echocardiographic images were obtained using a Philips IE33 equipment, with a 5-1 MHz Sector S5-1transducer. The quantification of cardiac chambers, hemodynamic measurements,tissue Doppler study and two-dimensional RTE were performed offline, using Q-Lab5.0 , a specific software for analysis of digital images, according to theprotocols of the American Society of Echocardiography.Echocardiographic measurements were taken three times, and the mean of thesevalues was recorded.Numerical data were described by descriptive analysis in tables, and expressed asmean, standard deviation and median.The Mann-Whitney test was used to assess differences in clinical variables ofECG, echo and two-dimensional STE between the paired groups. The normality ofvariable distribution was tested by the Shapiro-Wilk test. Significance levelwas set at 5%. Statistical analysis was processed with the SAS 6.11 software.Group 1 corresponds to patients with familial CA, according to the internationalcriterion for the disease - mean LV wall thickness ≥ 12 mm, diastolicdysfunction ≥ stage 2, or global longitudinal strain lower than -18%. Group 2corresponds to patients with familial extracardiac amyloidosis confirmed by biopsy.Group 3 corresponds to patients with TTR mutation with no evidence of CA. Group 4 isthe control group  and in the medial inferolateral segments in G1 (p=0.042).The same was observed in the basal inferoseptal (p=0.009), anteromedial (p=0.010),inferior medial (p=0.054), inferolateral medial (p=0.010) and apical septum(p=0.032) in G2, and in the basal inferoseptal (p=0.006), basal anterior (p=0.017),basal inferior (p=0.031), basal anterolateral (p=0.001), basal inferolateral(p=0.010), medial inferior (p=0.025) and apical anterior (p=0.013) in G4. It is ofnote that mean values of longitudinal strain were decreased in G1 not only ascompared with G3, but also in absolute values (<-18%). On the other hand,longitudinal strain of apical segments, even when decreased in relation to othergroups, was not decreased in absolute values.15 , G2(p=0.014) and G4 (p=0.0005). According to Baccouche et al. this parameter has adifferential diagnostic value between AC and HCM.When we evaluated global longitudinal strain in G1, the mean longitudinal strain inthe apical two-chamber, four-chamber and three-chamber views ,as well as the mean longitudinal tension were significantly lower than in G2, G3 andG4 groups.13 In addition,the longitudinal systolic rate was reduced in all 16 segments of left ventricle inCA patients, who did not have abnormal echo findings.19Serial analysis showed that systolic strain rate and strain at the basal and midventricle were significantly reduced in asymptomatic patients with increased LV wallthickness.20There are few studies showing functional changes in patients with CA usingtwo-dimensional STE. Sun et al. showed that global longitudinal strain detected bytwo-dimensional STE was significantly lower (12%) in CA patients as compared withhealthy controls, and also compared with patients with LV hypertrophy caused by HCMor hypertensive disease.21Liu et al. showed that the ejection fraction was preserved whereas longitudinalstrain was notably reduced in both compensated and decompensated patients .5 Patients in G1 had increased PR interval (mean of0.230s ± 0.060), which was significantly different from G2 (p=0.015), G3(p=0.044) and G4 (p=0.005). Sayed et al.22 also showed an association between disturbances inelectrical conduction and decreased longitudinal strain, and a negative prognosticvalue for this association, although the study was conducted with cardiac ALamyloidosis.Disturbances in electrical conduction are among the main clinical manifestations ofCA, and may be present in up to one third of patients.23Left atrial diameter was significantly greater in the G1 group (4.0 cm ± 0.18)than in G3 (p = 0.009), G2 (p = 0.009) and G4 (p= 0.0005). We also found increasedleft atrial volume in G1 in the apical four-chamber view (p=0.028), biplane(p=0.026) and indexed left atrial volume in the apical four-chamber view (p=0.010)as compared with G4. Such difference may be a sign of increased pressure in the leftventricle due to restrictive diastolic function, leading to pressure overload in theleft atrium.25Mean values of LV end-systolic diameter and end-systolic volume were significantlylower in G1  and G2  as compared with G4. LV end-systolic volume was also significantlylower (p=0.043) in G2 than G4. G1 showed mean LV end-diastolic diameter andend-diastolic volume significantly lower than G3 , and G4 . CA progresses with milddecrease in LV cavity.26Variables related to hypertrophy caused by amyloid deposit were statisticallydifferent between G1 and G3. Mean diastolic thickness of the interventricular septumin G1 was increased (1.17 ± 0.60 cm), and statistically greater than G3(p=0.041) and G4 (p=0.010). The same was observed with LV posterior wallend-diastolic thickness, with mean of 1.07 ± 0.39 cm in G1, which wassignificantly different as compared with G3 (p=0.010), G2 (p=0.033) and G4 (0.008).Mean values of interventricular septum was greater in G1 (1.17±0.60 cm) thanin G3 (p=0.041) and G4 (p=0.010). Mean wall thickness was significantly greater inG1 than in G3 (p=0.024) and G4 (p=0.011). Mean relative wall thickness was alsoincreased in G1 (0.600 ± 0.346) compared with G3 (p=0.026) and G4 (p=0.005).Our study shows a relationship between LV wall hypertrophy and severity of disease.Mean wall hypertrophy greater than 15mm has been shown as an independent negativeprognostic factor.23 Patients ofG2 also showed increased mean lateral E/E' ratio compared with G3 (p=0.020). LateralE'-wave velocity on tissue Doppler was also decreased in G2 as compared with G3(p=0.021). Medial and lateral E/E' ratio in G1 were increased  compared with G4.Amyloid deposits cause restrictive heart disease. The pattern of echocardiographicparameters of diastolic dysfunction classification tend to worsen with the diseaseprogression.27 showed statisticallysignificant difference in tricuspid annulus tissue Doppler analysis between patientswith CA, patients with extracardiac amyloidosis and healthy controls, and reported anegative prognostic value for right ventricular systolic dysfunction.Tricuspid annular S'-wave velocity on tissue Doppler is an index of right ventricularsystolic function, with normal values greater than 10 cm/s. Its mean values in G1was significantly different from G3 (p=0.036) and G4 (p=0003). Capelli etal.Two-dimensional STE increased the sensitivity of echo in diagnosing CA caused by TTRVal30Met mutation, since the adoption of a global longitudinal strain < -18%criterion increased the number of diagnosed patients from two (diagnosed by echo) tosix patients.


Cardiovascular magnetic resonance (CMR) is a versatile imaging modality that enables aetiological assessment and provides additional information to that of standard echocardiography in a significant proportion of patients with heart failure. In addition to highly accurate and reproducible assessment of ventricular volumes and replacement fibrosis, multiparametric mapping techniques have rapidly evolved to further expand the diagnostic and prognostic applications in various conditions ranging from acute inflammatory and ischaemic cardiomyopathy, to cardiac involvement in systemic diseases such as sarcoidosis and iron overload cardiomyopathy. In this review, we discuss the established role of T2* imaging and rapidly evolving clinical applications of myocardial T2 mapping as quantitative adjuncts to established qualitative imaging techniques. Cardiovascular magnetic resonance (CMR) has developed over several decades from an ancillary research tool to an evidence-based imaging modality that remains not only the gold standard assessment of cardiac morphology and ventricular function, but also has the additional benefit of in vivo tissue characterisation. Whilst limited in acutely decompensated states where patients may not tolerate lying flat, CMR plays a central role in the diagnostic evaluation and risk stratification of patients with heart failure , 2.recovery of the longitudinal component of magnetisation (the T1 relaxation time) towards equilibrium (‘spin-lattice’ coupling transferring energy out of the nuclear magnetisation) and the decay of the measurable transverse magnetisation (the T2 relaxation time) by irreversible effects (as opposed to others described later), known as spin-spin coupling. The T1 and T2 values vary depending on the composition of different biological tissues, primarily increased by greater water content, and these fundamental differences form the basis of intrinsic contrast used to generate images. Notably, cell cytoplasm is usually more laden with large molecules and tends to show shorter T2 than the usually purer interstitial fluid, although this is usually combined within a single MRI voxel as a complicated average . How. How7]. T2* relaxation represents the inherent decay of transverse magnetisation caused by a combination of spin-spin relaxation (T2) and magnetic field inhomogeneity (T2’), which in modern systems is dominated by tissue diamagnetic susceptibility-induced field distortions from the presence of paramagnetic materials such as iron. Gradient echo (GRE) sequences are optimised for T2* weighting by using a low flip angle, long echo time  to support T2* calculation) and, by definition, will not include a refocusing pulse to correct dephasing due to magnetic field inhomogeneity. A normal mean T2* value of above 40 ms has been widely reported in healthy volunteers . The preT2 mapping, or T2 transverse relaxation time mapping, is a technique used to construct a ‘parametric image’ or ‘map’ in which the intensity of each voxel is the output of a calculation performed independently at each corresponding spatial pixel from a series of input images. The map value reflects the calculated T2 relaxation time at each pixel. T2 maps can be analysed visually on a grey (or colour) scale but can also be analysed quantitatively by defining regions of interest relevant to the particular pathology being studied. Various different sequences have been used for T2 mapping. In principle, at least three separate single-shot images are acquired at increasing T2 preparation times to construct a transverse relaxation curve from these separate TE . This disrupts the local magnetic field homogeneity shortening T2* values with progressive ventricular dysfunction occurring below a T2* threshold of 20 ms . T2* valT2* has also effectively been used to monitor treatment response and assess the efficacy of iron chelation in a number of randomised trials . ImproveT2* monitoring is now internationally recommended based on these studies in the annual monitoring of transfusion-dependent patients at risk of developing myocardial iron loading . In thisAcute inflammatory cardiomyopathy is a clinical entity that generally requires endomyocardial biopsy to allow assessment of disease activity, characterised by the presence of myocardial oedema arising from inflammation-related increased capillary leakage. Whilst T2 mapping techniques have not received the same focus as T1 mapping in heart failure , a growiMyocarditis is an inflammatory disease of the myocardium which accounts for 12% of all sudden cardiac deaths on post-mortem studies . SpontanWhilst acute inflammatory cardiomyopathies, such as myocarditis, may be assessed by conventional T2-STIR sequences, quantitative mapping techniques allow greater delineation and may reveal myocardial injury not seen on conventional imaging sequences Fig. . T2 mappPatients with myocarditis often present with recent-onset heart failure with ongoing low-level myocardial inflammation . In thesSarcoidosis is a multisystem, granulomatous disease that most commonly affects young adults with cardiac involvement representing the second most common cause of death. Whilst late enhancement readily detects non-viable myocardial tissue , the detT2 mapping has been studied in a single retrospective review of 50 consecutive patients with histologically confirmed sarcoidosis undergoing CMR . AmongstAcute myocardial ischaemia and infarction are associated with myocardial oedema, although the former represents a potentially reversible injury. For this reason, there has been much interest in the role of T2-STIR to define the areas at risk following acute myocardial infarction  and seveMicrovascular obstruction (MVO) is known to represent an important clinical predictor of major adverse cardiac events following acute myocardial infarction . IntramyTakotsubo syndrome is an acute reversible heart failure syndrome with various anatomical variants and underlying pathophysiological mechanisms . MyocardCardiac inflammation in the setting of cardiac transplant rejection represents a diffuse process. One of the strengths of T2 mapping is the ability to identify prolonged T2 relaxation times in the absence of comparison with normal remote myocardium. Early studies have confirmed the positive correlation between prolonged T2 times and biopsy-determined grades of acute transplant rejection, but these approaches were limited by older sequence techniques based on spin echo at 0.5 T . There hCardiotoxicity from chemotherapy represents an important cause of morbidity and mortality amongst patients with cancer. Surveillance of LV ejection fraction during treatment is recommended but represents a late manifestation of cardiac disease, as in the case of iron overload. T2 mapping may offer a clinical tool with higher sensitivity than T2-STIR to detect and quantify subclinical cardiac disease secondary to chemotherapy use. A single study of nine patients receiving anthracycline-based chemotherapy showed that T2 values were elevated amongst those with cardiac disease detected by multigated acquisition scans . FurtherIn addition to exploring the role of T2 mapping across a range of cardiovascular diseases previously studied by T2-STIR, there is a major need to focus on defining normal ranges to evaluate the clinical impact of a regional or global T2 value within an individual patient. At present, various T2 mapping sequences are used across multiple vender-specific platforms. Whilst statistical analyses may demonstrate differences between patient groups and contribute to understanding disease processes and responses, there is unmet need to define the significance of a T2 value within a single patient to ultimately guide clinical management. This is exemplified by a similar evolution that occurred in T2* imaging.Elevated T2 signal representing oedematous myocardium may be assessed qualitatively by conventional T2-STIR imaging or quantitatively by T2 mapping, for which clinical evidence is emerging across the range of acute inflammatory cardiomyopathies. T2* signal arises from changes in tissue iron level and now serves as a routine clinical tool for assessing iron loading in myocardial and hepatic tissue. Whilst further outcome-based studies are required, T2 mapping is likely to impact routine clinical evaluation of patients with recent-onset heart failure given the ability to detect reversible myocardial inflammation.


Pulmonary hypertension (PH) is a progressive disease that results in right ventricular dysfunction through increased resistive afterload and pulmonary arterial (PA) stiffening. The ventricles are connected at the inter-ventricular sulcus, share an interlaced network of muscle fibers, and are hemodynamically dependent upon each other via the interventricular septum (IVS). Thus, the left ventricle (LV) plays a major role in RV contractile performance and may also be affected in this disease via ventricular-ventricular interaction. The relationship between hemodynamic parameters and torsion rate is unknown. We hypothesized that LV torsion rate is reduced in pediatric PH and is concomitant with hemodynamic markers of PH, and that this is due to the impact of prolonged increased impedance, resulting in reduced RV performance.Tagged cine CMR images were acquired for 8 pediatric PH patients and 18 control-matched subjects. LV systolic torsion rate (TR) was quantified using harmonic phase analysis. Right heart catheterization and echocardiography was performed on PH patients. Vascular ventricular coupling (VVC) was estimated with the single beat pressure-volume method and calculated as the ratio of arterial elastance to ventricular end systolic elastance (contractility).LV TR was significantly reduced in PH patients compared to control patients . LV TR correlated highly with mean pulmonary arterial pressure , RV systolic pressure , and pulmonary vascular resistance . VVC correlated highly with LV TR , as did RV contractility .Pediatric PH patients have reduced LV torsion rates compared to those of healthy patients, which could be significantly reducing RV contractile performance. Also, LV TR is strongly related to RV contractility and hemodynamic parameters derived by catheterization.


Iron overload-related heart failure is the principal cause of death in transfusion dependent patients, including those with Thalassemia Major. Linking cardiac siderosis measured by T2* to therapy improves outcomes. T1 mapping can also measure iron; preliminary data suggests it may have higher sensitivity for iron, particularly for early overload . We compared T1 mapping to T2* in cardiac iron overload.In a prospectively large single centre study of 138 Thalassemia Major patients and 32 healthy controls, we compared T1 mapping to dark blood and bright blood T2* acquired at 1.5T. Linear regression analysis was used to assess the association of T2* and T1. A “moving window” approach was taken to understand the strength of the association at different levels of iron overload.The relationship between T2* (here dark blood) and T1 is described by a log-log linear regression, which can be split in three different slopes: 1) T2* low, <20ms, r2 = 0.92; 2) T2* = 20-30ms, r2 = 0.48; 3) T2*>30ms, weak relationship. All subjects with T2*<20ms had low T1; among those with T2*>20ms, 38% had low T1 with most of the subjects in the T2* range 20-30ms having a low T1.In established cardiac iron overload, T1 and T2* are concordant. However, in the 20-30ms T2* range, T1 mapping appears to detect iron. These data support previous suggestions that T1 detects missed iron in 1 out of 3 subjects with normal T2*, and that T1 mapping is complementary to T2*. The clinical significance of a low T1 with normal T2* should be further investigated. Iron overload-related heart failure is the principal cause of death in transfused Thalassemia Major (TM) and other iron overload patients. ,2 Iron tT1mapping may help. –17 It coAll participants provided written informed consent for the study, approved by IRCCS Fondazione Policlinico CA' Granda Ethics Committee. The study was conducted accordingly to the 1975 Helsinki Declaration.Cardiac magnetic resonance (CMR) scans of 140 TM patients studied between July 2013 and February 2016 were analysed, along with matching CMR scans of 32 healthy volunteers (HV), i.e. subjects with normal CMR scan and without known chronic medical conditions or pharmacological therapy.Long- and short-axis, LV SSFP cine images, LV BBT2*, DBT2* and T1 mapping sequences (modified look locker inversion recovery–MOLLI–Siemens Works in Progress 448B) were acquired on an Avanto 1.5T scanner . For both DB and BB T2* sequences, the same single 10mm mid-ventricular short axis slice was imaged using a single breath-hold ECG-gated gradient multi-echo technique to generate eight images with a range of echo times , flip angle = 20°, FOV read/phase = 400mm/68.8%. The same slice was used for T1 images . Quality control of T1 maps was performed by review of the error maps generated with the sequence and review of the raw images.Two experienced operators independently analysed the scans. A single region of interest was manually traced in the interventricular septum avoiding the endo- and epicardial contours on the T1 maps. T2* measurements were carried out using the CMRTools “Thalassemia-Tools” plug-in . Signal intensity was plotted against each echo time and the T2* value was calculated from the resulting exponential decay curve. Truncation method was used to account for the plateau observed at the later echo times due to signal loss.  S1 Fig)S1 Fig).For each patient demographical and anthropometric information, transfusion regimen, chelation therapy, pre-transfusion haemoglobin and ferritin were collected.Descriptive statistics were expressed as mean±SD for continuous variables and as frequency distribution for discrete variables. To assess the association between DBT2* and either BBT2* and T1, a linear regression analysis was performed in a log-log scale. To detect where DBT2* and T1 association decreases, the determination coefficient was computed in a log-log scale with 30 samples of moving window over DTB2* with steps of 1 sample at a time. To smooth such series a low-pass filter based on moving average of order 3 was applied. Afterward, a new equispaced series was generated by linear interpolation. The linear regression fall was identified visually as the local maximum immediately before the large variation of the determination coefficient and the numerical value corresponding to that point was found by setting the first derivative equal to 0. Considering the methodology limits , which make impossible the definition of a sharp cut-off point, the numerical value obtained was rounded and used to identify an T2* values interval.An alpha level of 0.05 was used. All analyses were performed using R Core Team .All subjects underwent CMR without complications. Two patients and no HVs were excluded due to artefact in more than one sequence: DBT2* n = 3 (2%); BBT2* n = 4 (3%) and T1 n = 1 (<1%). In the patients’ cohort median DBT2* was 34.3ms (full range 3.8–52.8ms), median BBT2* 35.9ms (full range 4.2–77.7ms) and median T1 926ms . Normality for T2* was defined by the internationally accepted 20ms cut-point. The T1 normal range was defined by the HV cohort as 918-1015ms . Full range was 913-1050m. Using DBT2*, BBT2* and T1, 24 (17.4%), 21 (15.2%) and 76 (55%) patients had low values, suggesting cardiac iron overload. DBT2* and BBT2* were discordant in 7 patients with borderline iron overload . DBT2* and T1 were discordant in 52, always with a normal T2* and low T1, i.e. T1 mapping trebles the number of patients diagnosed with cardiac iron Figs . Below 2Using from now on only the DBT2*, T2* relationship with T1 was strong below 20ms and increasingly weak at higher T2*s. This paper provides novel information on a different ability of T1 and T2* in detecting cardiac iron overload. The internationally accepted cut-point for iron load assessment by T2* of 20ms is known to be conservative–prioritising specificity over sensitivity. In our study T1 mapping trebles the number of patients diagnosed with cardiac iron overload, while T2* missed 2 out of every 3 patients with such an abnormality . The T1 T1 mapping standardization is progressing rapidly with two series phantom experiments, in 40 and 69 centres respectively, worldwide, ,24 and cThe clinical relevance of mild iron overload missed by T2* has not been clarified yet. In our cohort, a 24-month follow-up was available for only 9 patients with normal DBT2* and low T1. Although no statistical consideration is possible due to the small number, in those patients an increase in LV end diastolic volume was observed (from 78±18ml to 84±15ml), suggesting a possible cardiotoxicity of even mild amount of iron, although EDV changes may also be influenced by anaemia. Further work is needed, particularly in high risk groups like children starting chelation or around pregnancy. Another key-step is to determine whether T1 can detect changes in iron loading earlier, particularly during iron accumulation, because this would enable clinicians to modify chelation therapy earlier.In conclusion, the potentially clinically relevant message we want to convey is that in the T2* 20-30ms range there might be iron load undetected by T2*. Thus, in such a scenario, T1 mapping could help, as it appears able to identify even small amounts of iron accumulating in the heart. Our observations, as well as their possible clinical implications, would need to be confirmed by future studies.S1 FigPanel A: example of DB T2* sequences, followed by analysis results by CMR tools–Thalassemia tools plug in. Panel B: example of a T1 images, followed by in-line generated T1 map; on the map, a single region of interest was manually traced in the interventricular septum avoiding the endo- and epicardial contours. ROI: region of interest.(TIFF)Click here for additional data file.S1 FileDemographical, CMR and clinical data for the TM cohort.(CSV)Click here for additional data file.


Myocardial salvage is currently being used as endpoint in several clinical trials and is determined by relating final infarct size to myocardium at risk (MaR). T2-weighted imaging (T2-STIR) cardiac magnetic resonance (CMR) has previously been shown to enable assessment of MaR up to one week after acute myocardial infarction. Recent experimental data indicate that the extent of MaR by T2-STIR varies over the first week which would have implications on how to design clinical cardioprotection trials using myocardial salvage as endpoint and in the clinical diagnosis of patients with myocardial infarction and normal coronary arteries.To investigate whether MaR as assessed by T2-STIR differs depending on scan day during the first week after the acute event in patients with reperfused first-time myocardial infarction.196 STEMI-patients from the MITOCARE and CHILL-MI trials undergoing acute percutaneous coronary intervention were included in the study. Eight additional patients with CMR on day 1 were also included. T2-STIR MR imaging was performed 1-7 days after the acute event and was used to evaluate MaR. Diagnostic quality on a scale from 0-3 and ability to correctly assign culprit vessel compared to angiography.There was no significant difference in MaR over the first week (p = 0.44, Figure Myocardium at risk by T2-STIR CMR imaging do not change in humans over the first week after acute reperfused myocardial infarction suggesting that MaR is a stable measure during this period of time.


The aim of this study was to investigate the potential of shear wave imaging (SWI), a novel ultrasound-based technique, to noninvasively quantify passive diastolic myocardial stiffness in an ovine model of ischemic cardiomyopathy.Evaluation of diastolic left ventricular function is critical for evaluation of heart failure and ischemic cardiomyopathy. Myocardial stiffness is known to be an important property for the evaluation of the diastolic myocardial function, but this parameter cannot be measured noninvasively by existing techniques.SWI was performed in vivo in open-chest procedures in 10 sheep. Ligation of a diagonal of the left anterior descending coronary artery was performed for 15 min  and 2 h . Each procedure was followed by a 40-min reperfusion period. Diastolic myocardial stiffness was measured at rest, during ischemia, and after reperfusion by using noninvasive shear wave imaging. Simultaneously, end-diastolic left ventricular pressure and segmental strain were measured with a pressure catheter and sonomicrometers during transient vena caval occlusions to obtain gold standard evaluation of myocardial stiffness using end-diastolic strain-stress relationship (EDSSR).In both groups, the end-systolic circumferential strain was drastically reduced during ischemia . SWI diastolic stiffness increased after 2 h of ischemia from 1.7 ± 0.4 to 6.2 ± 2.2 kPa (p < 0.05) and even more after reperfusion . Diastolic myocardial stiffening was confirmed by the exponential constant coefficient of the EDSSR, which increased from 8.8 ± 2.3 to 25.7 ± 9.5 (p < 0.01). In contrast, SWI diastolic stiffness was unchanged in the stunned group  which was confirmed also by the exponential constant of EDSSR .Noninvasive SWI evaluation of diastolic myocardial stiffness can differentiate between stiff, noncompliant infarcted wall and softer wall containing stunned myocardium. Assessment of diastolic left ventricular function is critical for the evaluation of heart failure and ischemic cardiomyopathy. Myocardial stiffness is thought to play a key role in diastolic function Recently, we developed shear wave imaging (SWI), a new ultrasound-based technique for quantitatively mapping the stiffness of soft tissues characterized by using the Young modulus defined by the slope of the stress-strain curve. This technique belongs to the field of multiwave imaging as it combines 2 waves: a shear wave providing stiffness contrast and ultrasonic waves providing millimeter-level spatial resolution The present study investigated the potential of SWI in vivo to noninvasively quantify changes in passive diastolic stiffness in an ovine model of ischemic heart failure in order to discriminate between infarcted myocardium and stunned myocardium. This is of upmost importance because in a clinical setting it is still challenging to differentiate between these 2 types of ischemia only by using strain echocardiographic evaluation of the regional active systolic function at rest.Animal procedures were approved by the Institutional Animal Care and Use Committee of Hôpital Européen Georges Pompidou (PARCC) according to the European Commission guiding principles (2010/63/EU). Ten sheep, weighing 49 ± 5 kg, were anesthetized with thiopental (0.5 ml/kg), intubated, ventilated at 15 ml/kg with 2% isoflurane, and given glycopyrrolate (0.4 mg intravenous) and vancomycin (0.5 g intravenous). A sterile lateral thoracotomy was performed. Vital signs, including heart rate, oxygen saturation, and arterial blood pressure, were monitored. The anterior wall at the middle left ventricular level was selected as the region of interest.The 10 animals were divided into 2 different groups. In group I (n = 5), acute myocardial ischemia was induced by ligating 1 diagonal branch of the left anterior descending coronary artery for 15 min, followed by 40 min of reperfusion. In group II (n = 5), acute myocardial ischemia was induced for 120 min, followed by 40 min of reperfusion. The objective was to achieve infarction in order to compare the stiffness of infarcted myocardium (group II) with that of stunned myocardium.c is the shear wave velocity, and ρ is the volume mass of the tissue. SWI is based on the remote generation of shear waves in soft tissue by acoustic radiation force combined with ultrasonic ultrafast imaging of the shear wave propagation, using the same ultrasonic transducer μ=ρc2wherStiffness measurements were repeated every 60 ms to quantify the dynamics of myocardial stiffness in real time. Fifteen acquisitions were performed, the total of which covered more than 1 cardiac cycle (∼600 ms). LV pressure and electrocardiography (ECG) were recorded at the same time on an external analog-to-digital board , allowing synchronization of the acquisition in post-processing. The end-diastolic time point was set at the onset of the QRS complex.LA . The end-diastolic thickness of the imaged wall was measured from the echocardiographic images recorded during the SWI acquisitions according to the latest recommendations of American Society of Echocardiography.Measurements of segment length were performed using a set of 2-mm sonomicrometer crystals . Two pairs of crystals were implanted near the endocardium for LV volume measurement. The first pair consisted of a crystal implanted at the base and the other at the apex of the LV for measuring the long axis LA . The seca and b are the internal and external radii, respectively, and P is the LV ventricular pressure. The term b was computed as the sum of a, and the thickness was measured by echocardiography.In current approaches, precise determination of passive myocardial elastic modulus requires measurement of end-diastolic stress-strain relationship. Strain was measured by sonomicrometry, whereas myocardial stress cannot be measured in vivo but only estimated by use of a geometrical model. A thick walled spherical model described by Mirsky and Parmley βε, where σ is the diastolic mid-wall circumferential stress, ε is the diastolic circumferential strain, and A and β are curve-fitting constants used to quantify passive stiffness End-diastolic segmental strain was plotted against end-diastolic circumferential stress for several cardiac cycles during vena cava occlusions. The diastolic stress-segmental strain relationship was approximated by the exponential equation σ = AeThe heart was explanted and sectioned into short-axis slices approximately 5 mm thick. The tissue was placed into 1% 2,3,5-triphenyl tetrazolium chloride (TTC) in phosphate buffer and incubated for 20 min at 37°C. The slices were then inspected visually to identify the presence of pale white infarcted tissues.t test to evaluate the significance of differences between individual mean values under different inotropic effects or after occlusion-reperfusion. When there was more than 1 comparison between means, ANOVA analysis was performed. If a significant trend was found by the ANOVA test, a Newman-Keuls test was performed to compare 2 different means. Statistical significance was inferred for a p value <0.05. Linear regression was used for correlation between systolic stiffness and contractility.Values are mean ± SD. Changes in myocardial stiffness were analyzed using a paired 2-tailed Student At baseline, end-diastolic SWI myocardial stiffness in group I (1.8 ± 0.3 kPa) was similar to that in group II (1.7 ± 0.4 kPa) as was stiffness constant measured by sonomicrometry  and systolic segmental deformation  . During Moreover, the diastolic stiffness constant measured invasively by sonomicrometry confirmed that end-diastolic stiffness increased strongly in infarcted myocardium and was unchanged in stunned myocardium . Figure This is the first study to quantify diastolic stiffness during myocardial ischemia by ultrasonography imaging and without the need of invasive sensors such as pressure catheters or sonomicrometer crystals. We demonstrated that reperfused infarcted myocardium has markedly increased diastolic myocardial stiffness which persisted after reperfusion. In addition, we showed that stunned myocardium preserved tissue compliance with no significant change of diastolic myocardial stiffness. As opposed to stiffness, regional systolic myocardial function significantly decreased in both groups.βε, relating the circumferential stress and strain term ε. This allowed us to compare diastolic stiffness measured by LV pressure and segment lengths from ultrasonic crystals with the end-diastolic stiffness measured by the SWI technique.In contrast to systole, for which there is a gold standard (end-systolic elastance) that can be obtained relatively easily, there is no universally accepted method for evaluating diastolic myocardial stiffness. During diastole, the myocardium becomes completely passive when relaxation is fully completed, and it was established in the early 1970s that passive properties of the myocardium could be defined by 3 parameters: stress, strain, and tangent modulus (elasticity or stiffness) SWI appears thus to be a valuable noninvasive technique in the evaluation of diastolic regional function which could be useful in the evaluation of regional ischemia. As described long ago with sonomicrometry, coronary occlusion in-vivo induced an immediate bulging of the ischemic segment with its net systolic shortening becoming close to zero or negative both in dogs In this study we have shown that a significant stiffening of the myocardium at end-diastole was observed in the infarcted group after 120 min of acute ischemia which further increased after 30 min of reperfusion. In contrast, passive myocardial stiffness was unchanged in the stunned group after reperfusion . AlthougWe can expect to use SWI in a post-myocardial infarction clinical setting to decide upon revascularization. Revascularization of significant coronary artery disease in a patient with LV dysfunction and symptomatic heart failure has been associated with improved cardiac function and cardiovascular outcomes Open-chest experimental and sonomicrometry crystals may affect myocardial deformation. Moreover, shear wave propagation may be affected by the particular boundary conditions of the open chest configuration. Specific boundary conditions of transthoracic imaging but also when fluids accumulate around the heart such as in pericardial or pleural effusion may affect the propagation of shear waves, and these particular situations need to be investigated further. For validation purpose, we used a simplistic thick-wall spherical model to compute the wall stress and evaluate the diastolic stiffness constant from the stress-strain relationship. In this study we chose 2 extremes (stunned and infarcted) to validate a concept. More studies are necessary to relate myocardial stiffness to infarct transmurality.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Myocardial stiffness is a major determinant of ventricular function both in heart failure and during ischemia. This parameter cannot be measured noninvasively by existing techniques. Successful evaluation of passive diastolic myocardial stiffness in vivo using noninvasive ultrasonography-based SWI can discriminate between stunned and infarcted myocardium, opening the door to noninvasive evaluation of myocardial viability.TRANSLATIONAL OUTLOOK: Noninvasive evaluation of myocardial stiffness by SWI still needs to be confirmed in human patients. We are currently starting a human study of normal volunteers and heart failure patients to validate this parameter in a clinical setting. Further study with longitudinal follow-up will be required to test the prognostic value of this new noninvasive parameter.In this study, we quantitatively assessed in vivo the passive myocardial stiffness using SWI in normal, stunned, and infarcted myocardium. SWI appears thus to be a valuable noninvasive technique in the evaluation of diastolic stiffness without the need of associated LV pressure measurement. A strong stiffening of the myocardium was found in diastole after infarction whereas end-diastolic myocardial stiffness remained unchanged in stunned myocardium. End-diastolic stiffness measured by SWI can thus also be used to determine the passive diastolic properties of ischemic/reperfused myocardium in an open chest configuration. The application of SWI to transthoracic imaging remains to be demonstrated in further studies.


Takotsubo syndrome is a recently recognized acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome. The typical takotsubo syndrome patient has a unique circumferential left (bi-) ventricular contraction abnormality profile that extends beyond a coronary artery supply territory and appears to follow the anatomical cardiac sympathetic innervation. The syndrome predominantly affects postmenopausal women and is often preceded by emotional or physical stress. Patients with predisposing factors such as malignancy and other chronic comorbidities are more prone to suffer from takotsubo syndrome. The pathogenesis of takotsubo syndrome is elusive. Several pathophysiological mechanisms involving myocardial ischemia , left ventricular outlet tract obstruction, blood-borne catecholamine myocardial toxicity, epinephrine-induced switch in signal trafficking, and autonomic nervous system dysfunction have been proposed. The syndrome is usually reversible; nevertheless, during the acute stage, a substantial number of patients develop severe complications such as arrhythmias, heart failure including pulmonary edema and cardiogenic shock, thromboembolism, cardiac arrest, and rupture. Treatment of precipitating factors, predisposing diseases, and complications is fundamental during the acute stage of the disease. The epidemiology, pathogenesis, and management of takotsubo syndrome are reviewed in this paper. Takotsubo syndrome (TS), also known as broken heart syndrome or neurogenic stunned myocardium, is a recently recognized acute cardiac disease entity . The terPrior to the introduction of the term takotsubo, the syndrome existed under different diagnoses. Since the introduction of the Japanese term takotsubo in 1990 , the synSeveral pathophysiological mechanisms for the development of TS have been proposed. The pathophysiology of TS is complex and may be multifactorial. The main proposed mechanisms are myocardial ischemia, left ventricular outlet tract obstruction (LVOTO), blood-borne catecholamine myocardial toxicity, epinephrine-induced switch in signal trafficking, and autonomics nervous system dysfunction with sympathetic nervous system hyperactivation including local cardiac sympathetic disruption and norepinephrine seethe and spillover.When Sato and Dote introduced the term takotsubo in 1990 , 18 to dMicrovascular dysfunction has been advocated by several investigators as a possible pathophysiological mechanism of LVWMA in TS . CoronarNoninvasive methods such as Doppler transthoracic echocardiography (TTE) and myocardial contrast echocardiography (MCE) can provide analysis of both LVWMA and coronary flow . StudiesIn a study of five patients with TS, Ibanez et al.  reportedAnother feature in TS, which could not be explained by the proposed ischemia hypothesis, is the cardiac myocyte histopathology. Contraction band necrosis is a characteristic histopathologic feature in TS that is distinct from coagulation necrosis, the fundamental histopathological sign in myocardial infarction –37. WortLVOTO has been observed in patients with TS. This may cause hypotension and may be one of the causes of cardiogenic shock in TS. El Mahmoud et al.  demonstrBlood-borne catecholamine myocardial toxicity has been suggested as one of the pathophysiological mechanisms of TS. This is based on the history of emotional stress preceding the disease onset in many patients with TS ; the repOn one hand, TS triggered by adrenal adenocarcinoma secreting high cortisol levels has been reported . On the Lyon et al.  in 2008 Investigators , 58, 59 The deep anguish that arises from bereavement and induces TS in an individual argues for an excessive sympathetic stimulation of the myocardium, likely mediated via the brain. Anecdotal histories related to death induced by emotions have been described for hundreds of years . The terAcute intracranial diseases such as intracranial and subarachnoid hemorrhage, thrombotic stroke, epilepsy, and others have been reported to induce TS –67. ThisPropranolol, which is a beta-adrenoceptor antagonist, has shown cardioprotective effects in patients with subarachnoid hemorrhage . NecrotiA low prevalence of diabetes mellitus in TS patients has been reported by several investigators. In a review of 959 studies, Madias  reported123I-MIBG) scintigraphy [11C hydroxyephedrine positron emission tomography (PET) [123I-MIBG. The principle finding from the analysis was decreased regional uptake of 123I-MIBG in hypokinetic/akinetic left ventricular segments with increased washout of 123I-MIBG.Signs of cardiac sympathetic denervation assessed by 123I-metaiodobenzylguanidine (tigraphy  and by 1hy (PET)  have beehy (PET)  reviewedInduction of brain death and subarachnoid haemorrhage in animal models and diverse types of intracranial diseases and injuries in humans have been reported to induce TS-like LVWMA . IncreasChemical myocarditis may be one phase in the course of myocardial pathological changes occurring in TS, most probably through local cardiac sympathetic overactivation-disruption and norepinephrine spillover , 83, 84.The LVWMA in TS has a characteristic systematized pattern. It affects the ventricular myocardium circumferentially with a sharp transition between the hypo/akinetic and the normal/hyperkinetic myocardial segments, resulting in a conspicuous left ventricular ballooning during systole . The heaHeart rate variability (HRV) analysis has been performed in both the acute phase and at follow-up of TS by several investigators . The indTS may be misdiagnosed as ACS because of the similarities in clinical presentation. TS should, therefore, be considered as a differential diagnosis in patients presenting with clinical features of ACS. TS may be triggered by, among others, intracranial hemorrhage or gastrointestinal bleedings and treating such patients with anticoagulation and fibrinolysis may result in life-threatening bleeding complications and death. Cardiogenic shock caused by LVOTO in TS may be misdiagnosed as cardiogenic shock due to extensive myocardial infarction and treated by catecholamine inotropics, which may result in augmentation of LVOTO and worsening of the cardiogenic shock with dismal consequences. Performing urgent coronary angiography, including left ventriculography, is essential to detect TS and to differentiate it from ACS because patients with TS have no coronary culprit lesion to explain the entire LVWMA seen in TS. Furthermore, the association between ACS and TS should not be missed since ACS may trigger TS . In womeIn almost one third of the patients, TS is triggered by physical stress, including serious medical or surgical conditions as sepsis, intracranial diseases, pheochromocytoma, and acute exacerbation of chronic obstructive pulmonary diseases , 15, 103A characteristic feature of TS is the spontaneous resolution of LVWMA in hours to weeks , 8, 100 Cardiogenic shock is an important and life-threatening complication in TS , 8, 15. There are no randomized studies on long-term treatment in TS. Observational studies have shown that the use of ACE inhibitors or angiotensin receptor blockers was associated with improved survival up to 1 year after the acute event. Such survival benefits have not been observed with beta-blockers . As ment


ECG demonstrated anterolateral T-wave inversion What is the most appropriate therapy? The correct answer is methylprednisolone. Echocardiography demonstrated an apical mass with obliteration of the left ventricular apex and extensive apical late gadolinium enhancement confirmed on CMR. Left ventricular function was preserved with no evidence of thrombus formation (see online 210.1136/heartjnl-2016-310611.supp1supplementary figure12-lead electrocardiogram.10.1136/heartjnl-2016-310611.supp2supplementary movieEchocardiography video loop in modified four chamber view.10.1136/heartjnl-2016-310611.supp3supplementary movieCine magnetic resonance sequence in four chamber view.Hypereosinophilic syndrome with cardiac involvement has been characterised in three stages: an acute necrotic stage with eosinophilic infiltration, a subacute phase with thrombus formation overlying the disrupted endocardium and chronic fibrotic progression to a restrictive cardiomyopathy. In the acute stage, medical therapy for chronic systolic heart failure is not indicated in the context of preserved left ventricular function. Antibiotics are not indicated in the absence of bacterial infection. Endocardiectomy with preservation of the atrioventricular valve apparatus is advocated for advanced endomyocardial fibrosis to reduce ventricular filling pressures; however, it is not warranted during the acute phase.4The patient was treated with methylprednisolone and cyclophosphamide. After 12 months of treatment, she had fully recovered with resolution of her peripheral eosinophilia and cardiac findings. Eosinophilic myocarditis has a high mortality rate, but early identification and treatment can lead to a regression of fulminant myocardial necrosis.