The aim of this study was to evaluate the diagnostic potential of a novel cardiovascular magnetic resonance (CMR) based multiparametric imaging approach in suspected myocarditis and to compare it to traditional Lake Louise criteria (LLC).CMR data from 67 patients with suspected acute myocarditis were retrospectively analyzed. Seventeen age- and gender-matched healthy subjects served as control. T2-mapping data were acquired using a Gradient-Spin-Echo T2-mapping sequence in short-axis orientation. T2-maps were segmented according to the 16-segments AHA-model and segmental T2 values and pixel-standard deviation (SD) were recorded. Afterwards, the parameters maxT2  and madSD (the mean absolute deviation (MAD) of the pixel-SDs) were calculated for each subject. Cine sequences in three long axes and a stack of short-axis views covering the left and right ventricle were analyzed using a dedicated feature tracking algorithm.LV) resulted in the highest diagnostic performance in receiver operating curve analyses (area under the curve [AUC] 0.84) when compared to any model containing a single imaging parameter or to LLC (AUC 0.79). Adding late gadolinium enhancement (LGE) to the model resulted in a further increased diagnostic performance (AUC 0.93) and yielded the highest diagnostic sensitivity of 97% and specificity of 77%.A multiparametric imaging model containing madSD and LV global circumferential strain (GCSLV and LGE yields superior diagnostic sensitivity in suspected acute myocarditis when compared to any imaging parameter alone and to LLC.A multiparametric CMR imaging model including the novel T2-mapping derived parameter madSD, the feature tracking derived strain parameter GCS Due to the heterogeneity of clinical presentations, the diagnosis of acute myocarditis remains one of the most challenging in cardiology . NeverthThe current gold standard, endomyocardial biopsy (EMB) is limited by its periprocedural risks and the low diagnostic sensitivity due to the so-called sampling error , 4. As aHowever, the current “Lake Louise Criteria” (LLC)  for CMR-Myocardial strain parameters thereby represent new quantitative indices of cardiac deformation and are thought to be more sensitive markers of contractile dysfunction than left ventricular ejection fraction (LVEF). A decline in strain values has been shown to precede decreases in LVEF in many different diseases , includiMapping techniques yield absolute T1 and T2 relaxation times and thus offer a quantitative assessment of focal, but also diffuse myocardial tissue alterations. Their routine clinical use, however, is still hindered by one major limitation, i.e. the large overlap of average T1 and T2 times between healthy individuals and myocarditis patients –19, leadA small set of recent studies suggested that the future of diagnosing myocarditis will most likely be a multiparametric imaging approach combining several of the novel quantitative parameters within a single imaging protocol , 13, 21.n = 67).After obtaining approval by the local institutional review board, data sets of 86 patients who had been consecutively referred to our department for CMR imaging after clinical diagnosis of acute myocarditis  were retrospectively analyzed. The clinical diagnosis of myocarditis was based upon the clinical suspicion of acute myocarditis and on the clinical criteria in the current recommendations   using a standard five-element cardiac phased array coil and a 4-lead vectorcardiogram. A balanced steady-state free precession (b-SSFP) sequence in breath-hold technique and with retrospective ECG-triggering was acquired in three horizontal long axes and a stack of short axes (SAX) covering the left ventricle (LV) for functional analysis and subsequent Feature Tracking analyses. Imaging parameters were chosen as previously described . VolumetIn patients and controls, edema-sensitive black blood T2-weighted images with fat saturation were acquired in SAX orientation covering the entire LV . MyocardT2-mapping data were acquired in 3 SAX slices evenly distributed across the LV  using an ECG-triggered, breathhold Gradient Spin Echo technique (GraSE) . Image pImage analysis of LLC was performed using a standard post-processing platform . The myocardium was evaluated for presence of myocardial edema on T2-weighted black-blood imaging visually as well as by calculating the T2-ratio  as previously described , 28. ForAll analyses were blinded with respect to the status “healthy” or “myocarditis” of each individuum. T2-maps were calculated with a dedicated plug-in written for the OsiriX viewer for Mac OS X  as previously described . The myoTwo statistically derived parameters of myocardial T2 and pixel-SD were calculated, aiming at reflecting the increased tissue inhomogeneity in the case of myocardial inflammation : a) the FT was performed offline based on the acquired bSSFP cine images and using a dedicated software . All analyses were blinded with respect to the status “healthy” or “myocarditis” of each individuum. Endocardial contours were drawn manually in end-diastolic images with subsequent software-driven automatic tracking of the endocardial contour throughout the entire cardiac cycle. The quality of automatic tracking was checked and contours were manually adjusted and tracking repeated were deemed necessary. The four-chamber view was used to derive right ventricular (RV) and LV longitudinal strain and strain rate (SR) values. Circumferential strain and SR parameters of both RV and LV were determined in short axis view at a basal, midventricular and apical level of the ventricle as previously described . AfterwaStatistical analysis was performed in R 3.1.2 , using tp-value of < .05 was regarded as statistically significant. Testing for significant differences between patients and controls was performed using Wilcoxon sum rank test or Welch independent T-test, depending on normality distribution of the data. Classification models were built using multiple logistic regression analyses. Models were compared according to the Akaike Information Criterion . Optimal cut-off values were defined using classification trees as previously described [All continuous data are given as mean ± standard deviation. A escribed . The diaLV) and SR, and LV global circumferential strain . When using different strain parameters in combination, all models revealed collinearity of the selected strain parameters, as either one was only significant in the model when the other one was not included. ROC-analyses finally revealed an only moderate potential in differentiating healthy controls from myocarditis patients for the three LV strain parameters . The model combining madSD and maxT2 as previously recommended  resultedIn ROC analyses, madSD resulted in the highest area under the curve (AUC) when compared to the other three T2 parameters Fig.  and all All single LLC demonstrated only a moderate potential for discriminating between patients with suspected myocarditis and healthy controls Fig. . A visuaFinally, different multiparametric imaging models were tested in a sequential fashion in order to evaluate, which combination exhibits the highest diagnostic potential in suspected acute myocarditis.LV or GCSLV performed better than the model containing madSD alone (AIC 66.55 for madSD + GLSLV and 68.12 for madSD + GCSLV).Multiple logistic regression analyses showed that models containing madSD and either GLSLV resulted in the highest diagnostic performance  resulted in a cut-off of ≥1.8 ms for madSD, of ≥ −25% for GCSLV and LGE positive. Using these cut-offs in combination led to an excellent diagnostic performance (Table LV without gadolinium (LGE) led to a still excellent discriminatory performance  who would have been missed by LLC. Finally, this study is the first offering dedicated cut-off values for all diagnostic parameters included in the multiparametric imaging models  in their small patient cohort, which might be due to the fact that they did not differentiate patients on the basis of LVEF and thereby introduced LVEF as a biasing factor.In the present study, GLSpatients  as well patients , we now s et al. . They deLV exhibited a slightly higher diagnostic potential than GLSLV, either when used alone or in combination with madSD ± LGE. Nevertheless, the differences between the diagnostic potential of the two LV strain parameters was only small and there might be a role for both parameters in the diagnostic algorithm of suspected acute myocarditis, as already proposed by other groups [LV as compared to GLSLV [LV in future diagnostic approaches.In the present study, GCSr groups , 16. Howto GLSLV , 39 as wLike in the initial proof of concept  and the Interestingly, combining madSD with maxT2 in a model revealed some collinearity between the two parameters in the present study and unlike the results of our previous studies, combining madSD with maxT2 in the present study cohort was not superior to using madSD alone as a predictor. As maxT2 represents a parameter, which might be more prone to outliers e.g. related to artifacts  , using mLV and LGE missed only 2 patients with suspected acute myocarditis (compared to 28 missed by LLC). This parallels the results of Luetkens et al. [Although madSD alone already yielded an excellent diagnostic performance in the present study cohort, the proposed multiparametric models exhibited an inherent potential to further improve the diagnosis of suspected acute myocarditis. Using the best multiparametric model in the present study, i.e. the combination of madSD, GCSs et al.  who receLV exhibited an excellent diagnostic performance in our study cohort, missing only 5 patients with suspected acute myocarditis. This approach might prove especially advantageous in patients with contraindications for the use of gadolinium-based contrast agents. In addition, there is a particular need for a diagnostic tool allowing an identification of LGE-negative subjects with acute myocarditis [Even without the use of gadolinium, the combination of madSD and GCScarditis .We tested the diagnostic performance of different parameters in myocarditis patients compared to a group of healthy subjects. However, the most relevant challenge for the novel quantitative CMR parameters will be their discriminative power in myocarditis patients when compared to patients with other non-inflammatory cardiomyopathies  or betweThe present study has several limitations. First, there are inherent drawbacks of the retrospective study design. Future larger (and multicenter) studies with a prospective selection of patients with suspected acute myocarditis should be performed in order to validate the presented proof of principle experiment of a novel multiparametric imaging approach. In addition, further studies should also evaluate the discriminatory power of the presented multiparametric imaging approach in order to differentiate between patients with acute and chronic forms of myocarditis as well as between other types of cardiomyopathy.The present study was performed using a clinical reference standard of myocarditis patients and we did not perform EMB. However, EMB is unnecessary or even contraindicated in myocarditis patients with normal systolic function . Hence, The results concerning the novel T2 parameter madSD still must be considered as preliminary. As so far only two studies have investigated the diagnostic potential of madT2 in myocardial inflammation, this needs further validation or re-estimation in larger prospective, multi-center studies.LV and LGE yields superior diagnostic sensitivity in suspected acute myocarditis when compared to any imaging parameter alone and to LLC.A multiparametric imaging model including the novel T2-mapping derived parameter madSD, the feature tracking derived strain parameter GCS


Cardiac rupture often occurs after myocardial infarction or chest trauma with a high mortality rate. However, left ventricular rupture caused by radiofrequency catheter ablation (RFCA) is extremely rare.We describe a case of a 61-year-old male who survived from left ventricular rupture caused by a RFCA procedure for frequent ventricular premature contractions. Surgical exploration with cardiopulmonary bypass (CPB) was performed when the signs of cardiac tamponade developed 7 hours after the ablation surgery.Teflon-buttressed sutures of the tear in the left ventricular posterolateral wall and pericardium patch applied to the contusion region on the wall repaired the rupture safely and effectively.Timely surgical intervention under CPB facilitated the survival of the patient. Teflon-buttressed sutures plus pericardium patch achieved the successful repair of the rupture. We describe a case of a 61-year-old male who survived from left ventricular rupture caused by RFCA. Rapid surgical salvage under cardiopulmonary bypass (CPB) was critically instrumental in saving his life without any complication . Since chest X ray showed no sign of hydropericardium, vagal reflex was considered first. There was no improvement of blood pressure after rapid fluid infusion, and 2 mg atropine was administered intravenously. Fluoroscopy again showed increased heart shadow, and transthoracic echocardiography revealed hydropericardium. Protamine was administrated intravenously to neutralize heparin. The patient then underwent pericardiocentesis drainage immediately, and 800 mL blood was drained off. Afterward, the chest tightness got better and the blood pressure increased (120/75 mm Hg). Since the patient remained hemodynamically stable for 40 minutes in the catheterization room, he was transferred to the ward and observed carefully. Two hours later, he felt tight in the chest again, blood pressure 95/70 mm Hg, heart rate 85 bpm, and auscultation of the heart found a far low blunt sound. We aspirated the indwelling catheter in the pericardium again and drained off 750 mL blood. Volume expansion and dopamine were administrated to sustain the blood pressure in normal. However, the patient had circulatory unstability again 1 hour later. The transthoracic echocardiography showed a left ventricular wall rupture and a hematoma in the left ventricular wall, which was smaller during systole period due to the contraction of the myocardium (Fig. 2 area of contusion in the posterolateral wall. A 5-cm tear of the epicardium was found at the center of the contusion near the apex, and 1 cm of the tear penetrated into the whole wall. Teflon-buttressed sutures were used to close the tear. Furthermore, a pericardium patch of sufficient size was applied to the contusion region using continuous sutures around and bioglue inside (Fig. The patient was transferred to the operating room for surgical exploration quickly due to active bleeding of the heart. Median sternotomy was performed. The pericardium cavity was filled with a large amount of blood and clot. After evacuating the pericardium cavity carefully, fresh blood was noted to be coming out of the left side of the heart, and the motion of the left ventricular free wall was hypokinetic. CPB was established with cannulation of the ascending aorta and right atrium quickly. After the cardioplegic arrest, further exploration of the heart revealed a 6 × 8 cmide Fig. . The patide Fig. .The case study was approved by the Ethic Committee of Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. Informed consent was obtained from the patient before data collection.3–5 RFCA has been reported with a low incidence of complications, among which access site vascular injuries are the most frequent. Other complications including cardiac tamponade, atrioventricular block, thromboembolic event, and coronary artery injuries are quite rare. Cardiac rupture secondary to RFCA is extremely rare that has barely been reported in the literature. Kono et al reported a case of successful salvage of left ventricular rupture caused by RFCA with timely surgical treatment. In their opinion, a small leak from friable myocardium in the ablation site caused oozing into the pericardium cavity and finally progressed to a “blow out” rupture. In our case, the RFCA energy caused damage to myocardium resulting in a contusion region and a slit in the left ventricular wall. Hypotension in the catheterization laboratory was considered for the first time due to hypokinesis of cardiac motion, since no hydropericardium sign was found. Continuous bleeding from the slit resulted in the subsequent hemodynamic instability and further enlargement of the wound.RFCA has emerged as a definitive option to treat patients with cardiac arrhythmia. It is currently being used as a nonpharmacologic alternative for refractory premature ventricular contractions with a beneficial effect.–10 Although sutureless repair without extracorporeal circulation has been reported in cases of cardiac rupture after myocardial infarction recently,,12 the classical approach to repair the rupture site under CPB is performed in the life-threatening situation. Since active bleeding of the heart was suspected before the operation, CPB was desperately needed during the surgery for stabilizing the hemodynamic state. Furthermore, an empty, relaxed cardiac condition is much more beneficial for secure repair. After opening the pericardium, fresh blood was noted to be coming out of the heart, and left ventricular rupture was confirmed. During the surgery, CPB guaranteed the safe repair of the rupture and avoided circulatory deterioration. After closing the tear with teflon-buttressed sutures, we applied a pericardium patch to overlay the contusion region to enhance the friable myocardium, which may prevent the ventricular wall from rupturing again.It is critical to take prompt surgical intervention once conservative treatment did not work. Cautious observation and expeditious diagnosis were needed to recognize the indications for emergency surgical exploration including cardiac tamponade, continuous bleeding, and hemodynamic instability.In conclusion, we describe a case of a 61-year-old male who survived from left ventricular rupture secondary to RFCA. Expeditious surgical intervention under CPB facilitated the survival of the patient without any complication. Teflon-buttressed sutures of the tear and pericardium patch of the contusion region achieved the successful repair of the rupture.The authors specially thank the staff of the Department of Echocardiography and Radiology for the diagnosis of the disease.


Spatial variation of restitution in relation to varying stimulus site is poorly defined in the intact human heart. Repolarization gradients were shown to be dependent on site of activation with epicardial stimulation promoting significant transmural gradients. Steep restitution slopes were predominant in the normal ventricle. endo) and left ventricle (LVendo), and an LV branch of the coronary sinus (LVepi) for transmural recording. S1–S2 restitution protocols were performed pacing RVendo apex, LVendo base, and LVepi base. Overall, 725 restitution curves were analyzed, 74% of slopes had a maximum slope of activation recovery interval (ARI) restitution (Smax) > 1 (P < 0.001); mean Smax = 1.76. APD was shorter in the LVepi compared with LVendo, regardless of pacing site . Basal LVepi pacing resulted in a significant transmural gradient of RT , due to loss of negative transmural AT-APD coupling (mean slope 0.63 ± 0.3). No significant transmural gradient in RT was demonstrated during endocardial RV or LV pacing, with preserved negative transmural AT-APD coupling . Steep ARI restitution slopes predominate in the normal ventricle and dynamic ARI; RT gradients exist that are modulated by the site of activation. Epicardial stimulation to initiate ventricular activation promotes significant transmural gradients of repolarization that could be proarrhythmic.The spatial variation in restitution properties in relation to varying stimulus site is poorly defined. This study aimed to investigate the effect of varying stimulus site on apicobasal and transmural activation time (AT), action potential duration (APD) and repolarization time (RT) during restitution studies in the intact human heart. Ten patients with structurally normal hearts, undergoing clinical electrophysiology studies, were enrolled. Decapolar catheters were placed apex to base in the endocardial right ventricle (RV Spatial variation of restitution in relation to varying stimulus site is poorly defined in the intact human heart. Repolarization gradients were shown to be dependent on site of activation with epicardial stimulation promoting significant transmural gradients. Steep restitution slopes were predominant in the normal ventricle.cardiac restitution describes the dynamic interaction between activation time (AT), action potential duration (APD), and repolarization time (RT) in relation to a given extrastimulus cycle length or diastolic interval (DI). It is hypothesized that a steep APD restitution slope may be proarrhythmic  apical pacing, when early engagement of the Purkinje network occurs , 62. ThiThis study aimed to investigate the effect of varying the stimulus site on the spatial apicobasal and transmural properties of AT, APD, and RT, during restitution studies in patients with structurally normal hearts. We also sought to evaluate the effect of this on AT-APD coupling and the steepness of the APD-restitution slope. Our findings suggest that APD does not adapt when varying the stimulus site to the LV epicardium and basal LV endocardium, resulting in significant repolarization gradients, due to loss of negative AT-APD coupling , 41, 45.Ten patients  with structurally normal hearts who were due to undergo diagnostic electrophysiology study (EPS) for investigation of palpitations or ablation for supraventricular tachycardia were enrolled into the study. Studies were performed in the postabsorptive state under minimal conscious sedation. Six patients underwent ablation to the slow pathway as part of their clinical procedure, in the remaining patients EPS alone was conducted. All patients had normal resting electrograms with no evidence of latent preexcitation, normal echocardiograms, and normal cardiac examinations. All anti-arrhythmic drugs were stopped for 5 days before procedure. The study was approved by the local ethics committee and conformed to the declaration of Helsinki. All patients gave informed consent. The research restitution protocol began after a 20-min period of resting sinus rhythm at the end of clinical EPS.endo) for recording in an apicobasal orientation (endo) for recording in an apicobasal orientation in the LV via the retro-aortic approach and a steerable decapolar catheter  was placed on the epicardium of the LV (LVepi) via the lateral cardiac vein via the coronary sinus (CS) for recording transmurally across the LV wall  was placed in the RV endocardium  at 1,000 ms. The S1-S2 coupling interval was then decremented in 50-ms steps until an S2 of 400 ms, then by 20-ms intervals between 300 and 400 ms, and thereafter in 5-ms steps, until effective refractory period (ERP) of the tissue. At ERP an S2 stimulus at 10 ms + ERP was applied followed by further decrementing S2 in steps of 2 ms to confirm ERP.Steady state was achieved by pacing at basic cycle length of 600 ms for 3 min. Following this, an Stmin) (A and B) . The Wyatt method was chosen because of its firm theoretical and experimental basis. It is established as the most accurate surrogate measure of local RT in the unipolar electrogram in experimental (2 (ATS2 − ATS1) and then subtracting the median ARI for the preceding S1 train after discarding the first three beats. This was done to minimize the effect of ARI dynamics on DI and to obtain a reliable DI even for very short S1–S2 coupling intervals.Unipolar electrograms were filtered at 0.05–500 Hz and recorded at a sampling rate of 2,000 Hz  A. Local tmin) , A and BA and B) . Local RA and B) , as the B) tmax, , A and Brimental , 25, 59 rimental , 49 and rimental B 10). D. Dtmin) Drive trains that contained ectopic beats were excluded. Signals at the pacing site or where it was not possible to calculate local RT due to abnormal T-wave morphology or ST segment elevation with no clear upstroke were excluded. In four patients, CS pacing was excluded in analysis due to inadequate epicardial capture for complete restitution curves to be generated. Recordings characterized by a signal-to-noise ration lower than 13 dB were discarded.Smax) was characterized by plotting ARI vs. DI for each restitution curve and defined as the steepest slope using piecewise linear regression on a moving 40-ms window, as previously described . AT, ARI, and RT were calculated semiautomatically using a custom-made MATLAB interface, as in previous studies , 58, andescribed .endo and LVendo within each patient  (44a). Continuous parametric data are presented as means ± SD, or, in the case of nonparametric data, median, unless otherwise specified. One-sampled Student's The shape of the restitution curve across a series of six RV catheter poles during RV pacing for a representative study patient is shown in P < 0.001), with a mean Smax = 1.76 and median Smax = 1.54. Smax grouped by recording and pacing sites. The median Smax was >1 in all instances. Smax was significantly >1 (P < 0.05) for all regions, except in the LVepi, when performing restitution from the RV apex (P = 0.26) and LV basal endocardium (P = 0.13). Smax was greater (endo (mean Smax = 2.2) compared with the RVendo  and LVepi , and there was no significant difference in the mean slope between the RVendo and LVepi, irrespective of pacing site. The same pattern was noted with RV apical and LV basal pacing with steeper Smax throughout the LVendo compared with the RVendo and LVepi (B and C). During epicardial LV pacing, Smax was steepest in the LVepi and LVendo, with no significant difference between the regions on ANOVA , but significantly greater Smax for both regions compared with the RV . Thus there was no consistent relationship between steepness of the restitution curve and distance from pacing site.A total of 725 individual restitution slopes complied with data quality criteria and were analyzed: 290 slopes from the RV, 290 slopes from the LV, and 145 slopes from the epicardium; 74% of slopes had a maximum slope > 1  showed initial activation of the apex and then base of the RV with minimal delay, followed by almost simultaneous activation of the apex and base of the lateral wall of the LV, and finally epicardial activation. AT restitution when pacing the base of the LVendo (D–F) had the expected earliest activation of the LV base, followed by delayed conduction to the LV apex and transmurally to the basal LVepi, followed by almost simultaneous activation of the RV at the base and apex. Pacing from the basal LVepi (G–I) resulted in earliest activation of the epicardium of the LV, followed by basal endocardial LV activation. This was followed by activation of the LV apex and then activation of the RV initially at the base and then the apex. All slopes displayed the expected finding of AT restitution with lengthening of AT at shorter cycle lengths close to the refractory period of the ventricle , but no significant apicobasal differences were observed, regardless of the site at which pacing was conducted. In the LVendo, restitution curves  again showed a trend toward shorter ARI at the base compared with the apex, regardless of pacing site, with significant apicobasal differences only when pacing the LV base endocardially , with shorter ARI epicardially than endocardially. The greatest transmural difference in ARI was measured when pacing the LV base epicardially .In the RV, restitution curves showed a trend toward shorter ARI at the base than at the apex ; with a 19-ms difference in RT at the apex compared with the base at the 50th quantile , with RT shorter at the base and longer at the apex. At the 50th quantile, apicobasal RT differences were 56 and 29 ms, when pacing the LV endocardially and epicardially, respectively.In the LVardially , E and HP < 0.01). At the 50th quantile, the epicardial RT was 77 ms shorter than the endocardium at the base of the LV. There was no significant transmural difference in RT during endocardial pacing from the RV apex and LV base (C and F).Significant LV transmural differences in RT were seen when pacing at the basal epicardium of the LV . During pacing at the LVepi, there was a loss of negative regional AT-ARI coupling, indicating that ARI increased with increasing AT.During RV pacing, regional negative AT-ARI coupling was preserved in the RV (−0.61 ± 0.3), in the LV (−0.42 ± 0.9), and transmurally (−1.36 ± 1.9). During pacing at the basal LVSmax > 1 predominates, regardless of stimulation site. Finally, although often studied and modeled in a monotonic exponential, our data confirm that the human restitution curve is triphasic in nature, as previously described .The presence of intrinsic APD heterogeneity within the ventricle has been shown in studies demonstrating electrical heterogeneity of channel expression , 48, 51.the base , 30. Thethe base , 17, 53,the base , A–C.A–C) and, therefore, the presence of negative regional AT-ARI coupling , with regional differences in ARI being maintained and inverse coupling, therefore, disrupted ; with 29-ms apicobasal dispersion in ARI .By varying the stimulus site, however, our data show that local ARI does not adapt to a change in activation sequence , D–I, wiisrupted . When bacoupling  as a rescoupling , B and Cn in ARI E during i pacing I, which i pacing , E and IE, H, and I). This has important implications both with regard to determining whether ventricular ectopy is benign and in relation to where ventricular tachycardia stimulation protocols are currently performed.The failure of AT-ARI coupling to adapt to a varying stimulus site by continuing to be negative brings into question whether negative coupling is a true electrotonic phenomenon, or a function of fixed differential channel expression within the ventricle, due to the effect of cardiac memory, for the normal activation sequence , 47, 48.Smax > 1 have been theoretically implicated in an increased risk of ventricular arrhythmia . M. Orini was supported by Marie Curie Fellowship (IEF-2013). P. D. Lambiase and P. Taggart were supported by the Medical Research Council (G0901819).No conflicts of interest, financial or otherwise, are declared by the author(s).N.T.S., M.O., R.B.S., R.P., R.B., E.R., A.W.C., P.T., and P.L. conception and design of research; N.T.S., M.O., R.B.S., R.P., F.K., O.R.S., G.B., R.B., E.R., S.A., A.W.C., M.L., and P.L. performed experiments; N.T.S. and M.O. analyzed data; N.T.S., M.O., R.B.S., R.P., F.K., O.R.S., G.B., R.B., E.R., S.A., A.W.C., M.L., P.T., and P.L. interpreted results of experiments; N.T.S. and M.O. prepared figures; N.T.S., M.O., R.B.S., R.P., F.K., O.R.S., G.B., R.B., E.R., S.A., A.W.C., M.L., P.T., and P.L. drafted manuscript; N.T.S., M.O., R.B.S., R.P., F.K., O.R.S., G.B., R.B., E.R., S.A., A.W.C., M.L., P.T., and P.L. edited and revised manuscript; N.T.S., M.O., R.B.S., R.P., F.K., O.R.S., G.B., R.B., E.R., S.A., A.W.C., M.L., P.T., and P.L. approved final version of manuscript.


Arterial hypertension is the commonest cause of cardiovascular death. It may lead to hypertensive heart disease (HHD), including heart failure (HF), ischemic heart disease (IHD) and left ventricular hypertrophy (LVH).According to the 2007 ESH/ESC guidelines, the recommended imaging technique is echocardiography (echo), when a more sensitive detection of LVH than that provided by ECG, is needed. Cardiovascular Magnetic Resonance (CMR), a non-invasive, non-radiating technique, offers the following advantages, beyond echo:a) more reliable and reproducible measurements of cardiac parameters such as volumes, ejection fraction and cardiac mass b) more accurate differentiation of LVH etiology by providing information about tissue characterisation c) more accurate evaluation of myocardial ischemia, specifically if small vessels disease is present d) technique of choice for diagnosis of renovascular, aortic tree/branches lesions and quantification of aortic valve regurgitation e) technique of choice for treatment evaluation in clinical trials.The superiority of CMR against echocardiography in terms of reproducibility, operator independency, unrestricted field of view and capability of tissue characterization makes the technique ideal for evaluation of heart, quantification of aortic valve regurgitation, aorta and aortic branches.CMR has a great potential in early diagnosis, risk stratification and treatment follow up of HHD. However, an international consensus about CMR in HHD, taking under consideration the cost-benefit ratio, expertise and availability, is still warranted. Arterial hypertension is the commonest cause of cardiovascular death. It may lead to hypertensive heart disease (HHD) including heart failure (HF), ischemic heart disease (IHD) and left ventricular hypertrophy (LVH). There is no consensus among new HTN practice guidelines as to target treatment of blood pressure (BP) among various subpopulations of patients. However, most guidelines now target a BP < 150/90 for patients >80y, a BP < 140/90 for patients with diabetes or CVD and a BP < 130/80 if diabetes, albuminuria, or high stroke risk is present. In United States, 1 out of every 3 adults has high BP. About 69% of people with first heart attack, 77% with first stroke and 74% with HF have BP higher than 140/90 mmHg [Essential hypertension accounts for 90% of adult cases and secondary causes of hypertension for the remaining 10%. According to the Framingham Study, hypertension accounts for about 1/4 of HF cases, and the risk of HF is increased by 2-fold in men, and 3-fold in women, respectively. Finally, hypertension affects other target organs including kidneys, eyes and peripheral arteries [Left ventricular hypertrophy (LVH) is the response of myocytes to various stimuli leading to myocytes’ hypertrophy, which occurs as a compensatory response to increased afterload . It is dVarious non-invasive techniques have been used to elucidate the pattern of HHD, including HFpEF. ECG and echocardiography were for many years the only techniques for evaluation of HHD. Although ECG measures of LVH were associated with cardiovascular disease risk in the Framingham study , the ECGRecently, a discrepancy documented in diagnostic performance and agreement on predictive ability suggests that LVH by ECG and LVH by CMR are likely to be two distinct phenotypes .Echocardiography has been successfully used in clinical trials and provided important knowledge in HHD . LVM assCMR, due to its excellent reproducibility, unrestricted field of view and non-invasive, non-radiating tissue characterization, became a powerful player for early diagnosis and treatment assessment of HHD and gender-specific values according to age and body surface area have been already published . The comSpeckle tracking (ST) alone or combined with tissue Doppler imaging (TDI) seems to be suitable for measurements of regional myocardial deformation and shows better agreement with CMR tagging for regional myocardial strain than measurements based solely on TDI; however, the clinical significance of the detected differences between the methods needs to be further established .According to the 2007 ESH/ESC guidelines the recommended imaging technique is echocardiography, when a more sensitive detection of LVH than that provided by ECG is needed, particularly in patients in whom organ damage is not detected by ECG, and in the elderly, in whom cardiac hypertrophy is frequent . AdditioCMR provides a comprehensive non-invasive, non-radiating evaluation of HHD, including accurate and reproducible assessment of biventricular function, valvular disease, inflammation and stress myocardial perfusion-fibrosis. Its extensive application has the potential to lead to better understanding of pathophysiology of HHD, promoting more accurate risk stratification and personalised treatment. However, the extensive application of CMR is hampered by serious limitations, such as long examination time, lack of availability and expertise, time consuming post-processing and high cost. As any diagnostic technique, CMR carries various limitations. Scanning patients with metallic clips, pacemakers and other non CMR conditional cardiac devices is not indicated, due to safety reasons. Furthermore, paramagnetic contrast agents can not be used in patients with reduced glomerular filtration rate (GFR) < 30 mL/min/1.73 m2, due to risk of nephrogenic systemic fibrosis (NSF) . If GFR Specific sequences for cardiac evaluation include steady state free precession (SSFP) cines for function and wall motion assessment, phase contrast sequences for velocity evaluation, T2-weighted short-tau inversion recovery (STIR) for oedema assessment, T1- and T2-weighted fast spin-echo for tissue characterisation, T1- weighted perfusion and myocardial late gadolinium enhancement (LGE) sequences and 3D–magnetic resonance angiography (MRA). Other more sophisticated CMR techniques such as myocardial tagging, T1, T2 mapping are at the moment part of research in HHD. Currently, 3D–gadolinium enhanced MR angiography (MRA) is considered the imaging technique of choice for evaluation of renovascular hypertension and MRI is also excellent to localize tumours leading to pheochromocytoma and primary aldosteronism. However, at the moment, no specific indications for CMR in HHD have been proposed .The main imaging technique for comparison with CMR remains echocardiography, since both computed tomography (CT) and nuclear techniques are not included in the routine evaluation of HHD and are used only if there are specific indications. Compared with these techniques CMR has the following advantages:CMR is more reproducible than both M mode and 2D echocardiography for the estimation of LVM, because it does not require geometric assumptions, according to data validated by animal studies –36. It pthe LIFE substudy in which the effect of high BP to ventricular remodelling was assessed the TELMAR study , which cthe LVH-4E , in whicthe ALIVE study , in whicthe ALLAY trial , in whicCMR or 3D echocardiography are the techniques of choice in trials evaluating LVM regression, because they allow the accurate detection of small changes of LVM in small patients’ cohorts, particularly when recruitment of large patients’ numbers is not feasible. CMR, due to its high reproducibility, can demonstrate reduction in LVM and volumes with normalization of LVEF after a short period of better blood pressure (BP) control using appropriate medication , 38 and CMR tissue tagging allowed the non-invasive assessment of intramyocardial displacement / strain by monitoring motion of specific material points spread in the myocardium –47. The In contrast, the echocardiographic evaluation of LV deformation is a geometry-based index, derived from linear measurements of the posterior and the septal wall and cannot distinguish between septal and posterior wall function. Thus, it is unknown, whether depressed LV deformation represents global or regional intrinsic depression of LV myocardial function in hypertrophy, due to pressure-overload . In addiDiastolic dysfunction is the earliest expression of HHD , 52, affThere is an excellent agreement between CMR and transthoracic echocardio-graphy for the assessment of diastolic inflow . CMR hasThe differentiation of aetiology of LVH is intriguing, because various forms of LVH may present with overlapping phenotypes. Various myocardial abnormalities including infiltrative diseases, hypertrophic cardiomyopathy (HCM), Fabry’s disease, cardiac sarcoidosis, aortic stenosis and athlete’s heart can be presented with LVH.CMR is superior to echocardiography for HCM diagnosis, by identifying areas of segmental hypertrophy  not reliably visualized by echocardiography (or underestimated in extent). High-risk HCM subgroups, identified with CMR, include those with thin-walled scarred LV apical aneurysms , end-stage systolic dysfunction and massive LV hypertrophy. CMR observations also suggest that the cardiomyopathic process in HCM is more diffuse than previously observed, extending beyond the LV myocardium to include thickening of the right ventricular wall as well as substantial morphologic diversity with regard to papillary muscles and mitral valve. These findings have implications for management in HCM undergoing invasive septal reduction therapy. Among HCM families, CMR has identified unique phenotypes of affected genetic status in the absence of LV hypertrophy, including myocardial crypts, elongated mitral valve leaflets and late gadolinium enhancement . CMR mayCMR can be also helpful in detecting changes in serial measurements of LV wall thickness after treatment with antihypertensives, in which regression of hypertrophy supports the diagnosis of hypertensive cardiomyopathy. In hypertensive patients, CMR documented reduced ejection fraction/anteroseptal systolic strains and increased cardiac chamber volumes/LV wall stress, while in HCM, revealed supernormal ejection fraction, reduced LV wall stress/longitudinal systolic strain and fibrosis. Increased LV wall stress was the hallmark of hypertension, while HCM was characterized by reduced total longitudinal strain. Finally, athlete’s heart was distinguished from other types of hypertrophy by using the CMR-derived diastolic wall-to-volume ratio . AlthougTo conclude, although ECG has high specificity for the detection of LVH, it is unable to identify the type of hypertrophy. This is because the ECG thresholds are generally selected to optimize specificity. Finally, standard ECG criteria for LVH have low sensitivity for CMR LVH, and few false positives and more false negatives.Echocardiography, although widely available and cost effective, carries the significant disadvantages of operator and acoustic window dependency and restricted field of view. In contrary, the CMR capability to offer detailed and highly reproducible wall motion evaluation without assumptions and concurrent tissue characterisation can significantly facilitate the differential diagnosis of various diseases presented with LVH.Myocardial fibrosis is the common end point of various pathologic processes in HHD and plays an important role in the development of diastolic dysfunction , 72. TheRecent studies proved that the severity of diastolic dysfunction increases in parallel with the extent of fibrosis, assessed by LGE . HoweverFinally, in well-controlled hypertensive patients, conventional CMR discovered significant underlying diseases , undetected by echocardiography. In these patients, T1 mapping revealed increased diffuse myocardial fibrosis, but this increase was small and only occurred with LVH . HoweverAlthough tissue biopsy is the gold standard for diagnosis of myocardial fibrosis, some circulating biomarkers have been also proposed for the non-invasive assessment of fibrosis. It was suggested that galectin-3  is associated with myocardial histological and molecular parameters related to fibrosis and with the circulating biomarkers of the extracellular generation of mature fibril-forming collagen types I  and III  in two independent studies of hypertensive patients with heart failure (HF). However, data from various studies are rather contradictory. The excess of cardiac and systemic Gal-3 in HF patients of hypertensive origin was not associated with histological, molecular and/or biochemical parameters related to myocardial fibrosis in these patients . FurtherIn HHD, coronary circulation changes take place, independently of occlusive atherosclerotic disease of epicardial coronary arteries. Furthermore, abnormalities in the coronary microcirculation, which accompany cardiac hypertrophy, play an important role in the pathophysiology of complications, attributed to LVH . AlthougStress perfusion CMR permits the non-invasive differentiation between hemodynamically significant coronary artery stenosis and microvascular disease, due to hypertension and/or diabetes, based on high temporal and spatial resolution of the technique. In small vessel disease, the perfusion defects are usually diffuse, circumferential, affecting ≤1/3 of the wall thickness and have shorter persistence (≤ 5 heartbeats) compared with those in patients with significant epicardial coronary disease  an inconclusive echocardiogram, b) a mismatch between clinical evaluation, ECG and echocardiography and c) severe, rapidly progressive LVH. Finally, due to high reproducibility, it is the ideal tool for clinical trials. In more details, the CMR indications in HHD are presented in Table HHD is the commonest cause of cardiovascular death with detrimental impact on patients’ morbidity and mortality and also health care costs. Although detailed guidelines determining the clinical indications of CMR in hypertension are still missing, CMR can provide early and highly reproducible evaluation of LVH and remodelling, not available by any other non-invasive technique; furthermore, the capability to perform tissue characterisation facilitates the early diagnosis and better risk stratification of micro-, macro-vascular ischemia and fibrosis, commonly found in hypertensive patients, with potentially high impact on their treatment and also on health care costs.Hypertensive heart disease (HHD) includesa) Left ventricular hypertrophy (LVH),b) congestive heart failure (CHF),c) ischemic heart disease (IHD)ECG evaluation of LVH lacks sensitivity and specificity, particularly in young male patients2D Echocardiographic assessment of LV mass (LVM) is useful in patients with severe LVH; however, it has high interobserver/interstudy variabilityLV mass assessed by RT-3DE correlates with CMR better than that determined by 2DE; however, underestimation and variability remain challenges in patients with ischemic cardiomyopathyCMR offers:a) High reproducibility of measurementsb) Easier and faster evaluation of treatmentc) Evaluation of intramyocardial functiond) Evaluation of Diastolic dysfunctione) Differentiation of various causes of LVHf) Fibrosis assessmentg) Ischemia detection


Background. Sorafenib, an oral tyrosine kinase inhibitor (TKI), targets multiple tyrosine kinase receptors (TKRs) involved in angiogenesis and tumor growth. Studies suggest that inhibition of TKR impacts cardiomyocyte survival. Inhibition of VEGF signaling interrupts angiogenesis and is associated with the development of hypertension and compensatory hypertrophy. Compensated hypertrophy ultimately leads to heart failure. Case Description. A 76-year-old man with a past medical history of systolic heart failure due to ischemic cardiomyopathy and stage IIIC hepatocellular carcinoma (HCC) presented with symptoms of decompensated heart failure. Four months prior to admission, he was started on sorafenib. Results. Our patient was treated with intravenous furosemide and guideline directed therapy. Clinical status was complicated by the development of low cardiac output and shock requiring inotropic support. Careful titration of heart failure medication led to hemodynamic improvement and discontinuation of dobutamine. Conclusion. Greater awareness of sorafenib cardiotoxicity is essential. As TKI usage grows for treatment of cancers, heart failure-related complications will increase. In our patient, routine heart failure management and cessation of sorafenib led to clinical improvement. Future studies on the treatment of sorafenib cardiotoxicity should be explored further in this unique patient population.  Sorafenib is an oral multikinase inhibitor that targets pathways involved in angiogenesis and tumor growth by inhibiting tyrosine kinase receptors and is recommended as a first-line drug for the treatment of advanced hepatocellular carcinoma due to limited alternatives. The effect of sorafenib on the human body is not limited to hepatocellular cancer cells and has been linked to cardiovascular toxicity leading to the pathogenesis of clinical heart failure and resistant hypertension , 2.This report presents the clinical case of a patient with ischemic cardiomyopathy and advanced HCC who was started on sorafenib and subsequently developed heart failure complicated by cardiogenic shock. We will review the clinical case, the biological basis for TKI cardiac toxicity, and the therapeutic challenges and considerations for the treatment of sorafenib-associated hypertension and heart failure.A 76-year-old man presented with worsening dyspnea at rest and on exertion, orthopnea, and lower extremity edema. The past medical history was significant for single-vessel coronary artery disease (s/p percutaneous coronary intervention), systolic heart failure with reduced ejection fraction (LVEF 37%) due to ischemic cardiomyopathy, severe ventricular hypertrophy, chronic atrial fibrillation, hypertension, hyperlipidemia, diabetes mellitus type two, chronic obstructive pulmonary disease, and Stage IIIC hepatocellular carcinoma. Family history was positive for hypertension and diabetes mellitus type two. He was previously treated with guideline directed therapy for systolic heart failure . The traEight months prior to admission, a cardiac MRI demonstrated findings suggestive of mild inferior wall myocardial ischemia on gadolinium imaging and moderately depressed systolic dysfunction. He was treated medically for ischemic heart failure without further risk stratification. Four months prior to admission, the patient was incidentally found to have a palpable right upper quadrant mass, which, by ultrasound, revealed a large heterogeneous echogenic density (measuring 13 cm). He underwent transhepatic biopsy and pathologic results were significant for poorly differentiated pleomorphic hepatocellular carcinoma. CT of the abdomen and pelvis was significant for tumor extension into the inferior vena cava and subdiaphragmatic space. A markedly elevated alpha-fetoprotein (AFP) level  was measured, suggestive of a high tumor burden.His WHO cancer staging was Stage IIIC based on clinical as well as imaging findings. The 1-year survival of Stage IIIC HCC is 6–8 months for patients and the recommended treatment is a tyrosine kinase inhibitor (TKI) called sorafenib, which extends median survival length to 10.7 months .The patient presented to the emergency department hypertensive (169/79 mmHg) and tachycardic with a ventricular rate of 127 beats per minute . The phyThe clinical exam was consistent with decompensated heart failure. The patient was treated with intravenous furosemide, carvedilol, and lisinopril. After sufficient diuresis (10 liters of fluid), clinical symptoms improved minimally . HoweverBased on the antecedent history of recent initiation of sorafenib followed by deterioration in cardiac function, sorafenib-induced decompensated heart failure was diagnosed. This case report serves as an example of the therapeutic challenges of heart failure management in patients treated for hepatocellular carcinoma with sorafenib. The cardiac toxicity of sorafenib is known and while many patients who have preexisting heart failure are not initiated on tyrosine kinase inhibitors for this reason, limited therapies for cancers such as HCC may compel care providers to do so. Cautious clinical decision-making, heart failure follow-up, and recognition of higher risk groups in this unique subset of patients are needed. It is our goal to discuss the mechanism of sorafenib-associated cardiac toxicity and other tyrosine kinase inhibitors. We also review clinical strategies for treatment of heart failure complications.Sorafenib is an oral tyrosine kinase inhibitor that targets multiple tyrosine kinase receptors involved in angiogenesis and tumor growth and is recommended as a first-line drug for the treatment of advanced HCC . In cancThe Signaling Pathway of Tyrosine Kinases, Sites of Inhibition, and Cardiotoxicity Secondary to Trastuzumab following Treatment of HER2+ Breast Cancer. To further understand the reasons for sorafenib-associated cardiotoxicity, it is relevant to discuss the lessons learned from earlier generation TKIs, the exact cellular pathways affected, and the mechanisms behind the pathogenesis of clinical heart failure. Patients with ERBB2 receptor, also known as HER2 , breast cancer that were receiving anthracycline-based chemotherapy were 3.5 times more likely  to develop asymptomatic cardiac dysfunction on echocardiography or clinical heart failure . RA. RA12]. The RAF-1 kinase also inhibits cell death pathways mediated by apoptosis signal-regulating kinase 1 (ASK1) as well as mammalian sterile 20 kinase 2 (MST2). Both ASK1 and MST2 are proapoptotic kinases and have roles in oxidant stress-induced injury. Deletions of RAF-1 in the heart result in ventricular dilation, reduced contractility, and increased cell death , 15. WheNonselective TKIs such as sorafenib that target multiple kinases have great potential for intracellular toxicity. Myocardial cells require greater energy demands than other cells and therefore are particularly sensitive to deficiencies in energy production. Some case reports have indicated the potential for reversibility of sorafenib-induced cardiomyopathy after discontinuation though it is unclear to what extent or after what duration of treatment that reversibility is still feasible .Mechanism of Cardiotoxicity after Treatment with Sorafenib May Be In Part due to VEGF Inhibition. TKRs were initially noted to enhance gene expression and protein synthesis involved in cardiac hypertrophy [p < 0.001) [ertrophy . Deleterertrophy , 20. Cliertrophy , 22. Amo< 0.001) . Therapeutic Challenges and Considerations in the Treatment of Hypertension. Hepatocellular carcinoma is one of the most common cancers in the world and typically presents in advanced stages. Standard treatments during early stages include partial hepatectomy, local ablation, and liver transplantation. Sorafenib is recommended as a first-line drug for the treatment of advanced HCC [nced HCC , 2.In the case of sorafenib-induced hypertension, blood pressure is treated with conventional therapy and appears not to impact or worsen progression-free survival among patients treated for metastatic RCC . Early iTherapeutic Challenges and Considerations in the Treatment of Systolic Heart Failure. Although it is typically recommended that chemotherapy be discontinued when significant heart failure develops, case reports have shown that sorafenib can be used to treat advanced HCC for as long as 12 months and may be reduced in those that develop heart failure [ failure , 28.In patients that develop clinical heart failure or systolic dysfunction on echocardiography, treatment with a combination of guideline directed ACE-I, and beta-blockers have been shown to reduce heart failure-associated mortality and improve cardiovascular morbidity . The mosDobutamine Treatment May Be Considered in Those with Severe Heart Failure. Baseline diminished contractile reserve with subsequent exposure to sorafenib led to the development of cardiogenic shock in our patient who was subsequently treated with dobutamine, an inotrope with weaker chronotropic effects, which successfully restored a normal hemodynamic profile. While it is well known that inotropic support is associated with adverse long-term cardiovascular outcomes, the clinical efficacy of inotropes after exposure to cardiac toxic medications is unknown. Dobutamine's pharmacologic function does not depend on tyrosine kinases but rather on G-protein coupled receptors. Whether sensitivity to beta-1 adrenergic activation by dobutamine is increased after tyrosine kinase inhibition is unknown. In response to isoproterenol, the presence of genistein was shown to potentiate beta-adrenergic sensitivity in the heart of animal models [l models .In our patient with underlying ischemic cardiomyopathy and advanced hepatocellular carcinoma, the management of heart failure in the setting of coexisting malignancy poses interesting and new clinical challenges. Sorafenib is a tyrosine kinase inhibitor that targets multiple tyrosine kinase receptors involved in angiogenesis and tumor growth. Unfortunately, sorafenib-associated cardiotoxic effects such as hypertension, reduced LVEF, and heart failure are of great concern and contribute to the challenging nature of HCC management. It is essential that TKI-induced hypertension be treated aggressively with standard treatments and regular monitoring. Guidelines also recommend echocardiogram monitoring for patients started on chemotherapeutic agents, especially those with cardiac risk factors, prior to treatment initiation, once heart failure symptoms develop, and after treatment completion. There are currently no specific recommendations for managing TKI-induced heart failure, and patients are typically managed with standard heart failure treatments. Beta-adrenergic effects of dobutamine may actually be potentiated by tyrosine kinase inhibition.We initially considered more common causes for heart failure exacerbation in our patient. Patients with restrictive heart failure often develop worsened heart failure symptoms due to sustained periods of atrial fibrillation with rapid ventricular response. Prior to hospitalization, however, the patient's ventricular rate was well controlled with beta blockade, and it is our belief that the interval decline in ventricular function led to increased left atrial pressure and presentation of atrial fibrillation with rapid ventricular response. Furthermore, there were no EKG abnormalities suggestive of myocardial infarction or evidence of severe valvular regurgitation on echocardiography. There was the possibility that overdiuresis due to an inability to accurately estimate the filling pressures on physical exam led to inadequate preload leading to low cardiac output shock. However, the patient's right heart catheterization reflected that the filling pressures remained elevated after diuresis and that the etiology of low cardiac output was mainly attributed to diminished contractility.After successful titration of guideline directed treatment and discontinuation of dobutamine, a repeat echo demonstrated baseline LV function. A repeat trial of sorafenib at a lower dose was offered to the patient but was declined. Although sorafenib is the potential predisposing factor for the patient's decompensation, the causal relationship between this drug and heart failure is still unclear since rechallenge was not performed. The patient was discharged home with palliative care follow-up for coordination of hospice.


While most patients recover from suspected acute myocarditis (sAMC) some develop progressive disease with 5-year mortality up to 20%. Recently, parametric Cardiovascular Magnetic Resonance (CMR) approaches, quantifying native T1 and T2 relaxation time, have demonstrated the ability to increase diagnostic accuracy. However, prognostic implications of T2 values in this cohort are unknown. The purpose of the study was to investigate the prognostic relevance of elevated CMR T2 values in patients with sAMC.n = 11) for 1-year-MACE and hospitalisation. A follow-up after 11 ± 7 months was performed in 98% of the patients. Global T2 values were significantly increased at acute stage of disease compared to controls and decreased over time. During acute disease, elevated global T2 time  as well as myocardial fraction with T2 time >80 ms  predicted occurrence of the combined endpoint. Patients with clinical recovery revealed significantly decreased T2 relaxation times at follow-up examinations; however, T2 values were still elevated compared to healthy controls.We carried out a prospective study in 46 patients with sAMC defined by current ESC recommendations. A combined endpoint was defined by the occurrence of at least one major adverse cardiac event (MACE) and hospitalisation for heart failure. Event rate was 24% (Assessment of myocardial T2 relaxation times at initial presentation facilitates CMR-based risk stratification in patients with acute myocarditis. T2 Mapping may emerge as a new tool to monitor inflammatory myocardial injuries during the course of disease. Myocarditis is a common cardiac disease with a prevalence of 22 per 100.000 people worldwide . In the Recent recommendations highlight the need for new diagnostic criteria in patients with suspected acute myocarditis (sAMC) and endorse coronary angiography as well as endomyocardial biopsy (EMB) during routine diagnostic workup , 6. BesiRecently, we demonstrated increased T2 values in patients with biopsy-proven acute myocarditis (bpAMC) compared to age and gender matched controls , 15. FurUntil now, several predictors of poor outcome have been identified, including reduced left ventricular ejection fraction (LVEF) , advanceThe aim of the presented study was to prospectively recruit patients with sAMC and conduct CMR and EMB as systematic as feasible in order to assess the prognostic value of T2 Mapping in this patient cohort. We hypothesized that T2 Mapping facilitates risk stratification in patients referred for CMR workup of sAMC. In particular, we sought to evaluate whether T2 Mapping provides additional prognostic information over conventional CMR parameters and identifies patients at high-risk for following adverse cardiac events.The ethical board of Heinrich-Heine University Düsseldorf approved the present study (application number 4307). All participants signed informed consent. The study complies with the declaration of Helsinki.Forty-six patients meeting inclusion criteria of sAMC according to ESC guidelines were prospectively enrolled between 2013 and 2016: clinical symptoms <14 days  and one additional diagnostic criterion in terms of ECG abnormalities , hsTNT-elevation or new global/regional wall motion abnormalities and exclusion of coronary artery disease.Exclusion criteria of the study were 1) coronary artery disease (coronary stenosis >50% proven by angiography 2) pre-existing other cardiac disease that could explain symptoms and 3) contraindications against CMR.n = 40, 72 ± 12 h after presentation).All patients underwent CMR between day 0 and day 5 after initial presentation at hospital. Right ventricular EMB was conducted whenever feasible  with a 32-channel phased array coil. After scout and reference scans, CINE-loops in continuous short axis slices covering the whole ventricle were analyzed to calculate left ventricular function and volumes.For edema imaging, a T2-weighted TSE-STIR sequence was used and T2 Mapping was conducted with a GRASE sequence in three short axis slices . This sequence combines the TSE and echo-planar imaging methods by using a train of refocusing 180° pulses and an odd number of additional gradient echoes for each spin echo. This sequence was used with cardiac triggering and respiration navigator gating with the following parameters: TR = 1 RR interval, number of echo images = 15, echo spacing 10 ms, leading to an echo train of 150 ms, number of gradient echoes for segmented acquisition = 3 (EPI factor), FA = 90°, spatial resolution: 2 × 2 × 10 mm3, parallel imaging (SENSE) with an accelerating factor of 2, k-space data acquired with Cartesian encoding scheme. For blood saturation a double inversion (black-blood) pulse was used [was used .Late Gadolinium Enhancement (LGE) imaging was performed eight to ten minutes after gadolinium contrast injection  using a 3-dimensional–gradient spoiled turbo fast-field-echo sequence with a non-selective 180° inversion-recovery pre-pulse triggered to end-diastole acquired in the short axis, 4–3- and 2-chamber view to cover the whole ventricle.For post-processing, left ventricular function and LGE were assessed off-line using a commercial software . LGE was evaluated by visual assessment and assignment of certain myocardial parts according to the 17-segment model of the AHA [ the AHA .2) could be used as a goodness-of-fit parameter in order to exclude accidental values. If R2 was not within a tolerance interval chosen to be 0.7-1, the corresponding T2 value was not considered for further calculations. The resulting T2 constants were colour-coded using the spectral look-up table. Endo- and epimyocardial region of interests (ROI) were drawn manually in the first echo image of the echo-train.T2 maps were generated according to Bönner et al. . T2 mapsThe myocardial ROI was segmented according to the AHA 17-segment model  and T2 vPatients were followed over time and a combined clinical endpoint was defined as a composite of major adverse cardiac events (MACE) and hospitalisation due to heart failure. MACE was defined as a composite of all-cause death, cardiac death, cardiac transplantation and ventricular assist device implantation. The length of follow-up was determined by occurrence of an endpoint or the last clinical follow-up examination.t-test. Welch’s correction was used when unequal SD was assumed. Bonferroni correction was applied for multiple comparisons. Fisher’s exact test was used to examine the significance of the association between two kinds of classification. Receiver operator characteristic (ROC) analysis was performed to generate threshold values with respect to optimal sensitivities, specificities and areas under the curve (AUC). Kaplan-Meier curves were calculated for visualizing cumulative event free survival of patients with global and regional T2 time exceeding several cut-offs. P-values below 0.05 were assumed to be significant.Statistical analysis was performed with Sigma Stat2010 (Systat GmbH) and GraphPad Prism 7. Unless otherwise stated, data are presented as mean value ± standard deviation. Data were statistically analysed by the paired or unpaired Student’s A total of 46 patients matched inclusion criteria. Table Forty-three patients underwent coronary angiography to exclude coronary artery disease (CAD). Another three patients (age < 35 years) refused invasive coronary assessment. Forty patients underwent EMB during initial workup. Within those 40 patients, 22 were characterized as having bpAMC.n = 46) vs. controls (n = 60): 42 ± 15% vs. 62 ± 8%; p < 0.001). LGE was present in 80% of all sAMC patients. T2 time was significantly elevated in patients with sAMC (sAMC (n = 46) vs. controls (n = 60): 68.1 ± 5.8 ms vs. 60.0 ± 4.2 ms; p < 0.001).  underwent follow-up examination after a mean interval of 11 ± 7 months. Eleven patients (24%) reached the combined endpoint: One patient died, one patient underwent heart transplantation and three patients received ventricular assist device implantation due to severe, therapy-refractory heart failure. Six patients were re-admitted to hospital for decompensating heart failure. Thirteen patients (29%) showed persistent left ventricular dysfunction. Mean LVEF at follow-up was 51 ± 13% with a mean absolute increase in LVEF of 10 ± 13%.n = 11) vs. clinical recovery (n = 34), global T2 time: 71.8 ± 5.7 ms vs. 66.8 ± 4.9 ms, p = 0.01; fraction with T2 time >80 ms: 27.5 ± 14.9% vs. 15.1 ± 8.7, p = 0.03) . In contrast 7 patients (21%) of those who recovered showed severely reduced LVEF at first presentation (Table n = 19) had mean LVEF of 34 ± 13% at initial presentation vs. patients with LVEF >55% at follow-up (n = 23) displayed an initial LVEF of 47 ± 13%, p = 0.003).Likewise, reduced left ventricular function at initial presentation was associated with an unfavourable outcome: Seven patients (64%) who experienced the combined endpoint presented with severely reduced LVEF LVEF <30%) .In a subset of patients 23/45) monitoring of T2 values over time was possible: Global T2 values were significantly increased at first presentation compared to follow-up examination and controls. In line with this, the extent of myocardium with T2 time above 80 ms was markedly larger in the acute phase of disease  vs. controls (n = 60), global T2 time: 64.4 ± 6.4 ms vs. 60.0 ± 4.2 ms, p = 0.001; fraction with T2 time >80 ms: 13.6 ± 13.3% vs. 4.1 ± 3.0%, p = 0.004). Furthermore, patients who reached the combined endpoint or presented with persistent left ventricular dysfunction at follow-up displayed persistently elevated T2 values compared to those who recovered completely. In contrast, recovery of LVEF went along with decreasing T2 values  Elevated global and regional T2 values in patients with sAMC predict MACE and rehospitalisation (b) Patients with normal T2 times compared to healthy controls are at low risk for adverse cardiac events (c) T2 values decline with clinical recovery of over time.Several studies reported that native T2 time is increased in patients with clinical diagnosis of acute myocarditis , 19, 20.The presented study demonstrates that measurement of global T2 time provides additional prognostic information and facilitates risk stratification in patients presenting with myocarditis. Kaplan-Meier curves generated among different groups of patients  showed a significantly shorter event-free interval in patients with global T2 time exceeding 4 SD. Furthermore, the percentage of myocardial fraction with T2 time above 80 ms was higher in patients, who reached the combined endpoint. On the other hand patients with normal T2 values were at low risk for following events.The fact that global T2 time at first presentation was significantly elevated in patients who experienced an adverse outcome  highlights the potential of T2 Mapping strategies to identify patients at risk. Assuming that an acute myocarditis is characterized by widespread cell damage, inflammation and edema, global T2 time yielded a higher odds ratio for predicting combined endpoint than the regional approach did. Furthermore, this study showed that an adverse clinical outcome was associated with the grade of elevation of global T2 time and amount of myocardial area with increased T2 values.T1 Mapping provides high diagnostic accuracy in confirmation and exclusion of myocarditis and also showed its ability to differentiate between different stages of disease activity , 21. RecLurz et al. demonstrated that T1 Mapping did not provide additional diagnostic information in patients with chronic symptoms, which could be explained by histological pathology . Acute iRecent data also confirm the value of ventricular function as an independent predictor of outcome in patients with acute myocarditis , 24. BivIn addition, presence of LGE is a controversial predictor of outcome in acute myocarditis. Grün et al. investigated a large population of patients with biopsy-proven viral myocarditis who also underwent CMR. In their study LGE was the best predictor for all-cause- and cardiac mortality . In lineIn a previous published study myocardial edema assessment by T2 weighted Imaging was a strong predictor for left ventricular function recovery . Vermes In a subgroup analysis (51% of sAMC patients), we accomplished follow-up CMR and demonstrated that T2 time was significantly elevated at initial presentation possibly reflecting acute stage of disease and declined during the healing process of myocarditis Fig. . In detaOur CMR protocol did not include Early Gadolinium Enhancement ratio (EGEr) for complete evaluation of the Lake Louise approach. Although complete Lake Louise criteria experienced general acceptance as the reference for CMR-based diagnosis of myocarditis, it has been reported that omission of EGEr does not alter overall diagnostic accuracy .Our study included a rather small sample size. However, we performed a very strict selection process according to current ESC guidelines. Furthermore 87% of patients underwent right ventricular EMB, confirming diagnosis of AMC in 55%.Another limitation of our study is that LGE was performed eight to ten minutes after gadolinium contrast injection, which could be not the optimal timing. Recently, Rodríguez-Palomares et al. emphasized that timing after contrast injection could be of prognostic importance in patients with myocardial infarction .Our results suggest that assessment of myocardial T2 relaxation times at initial presentation facilitates CMR-based risk stratification in patients with acute myocarditis. Patients with normal T2 values are at low risk for following adverse cardiac events. T2 Mapping may emerge as a new tool to monitor inflammatory myocardial injuries during the course of disease.


In recent years, catheter-based renal denervation (RDN) has been investigated as a promising strategy in the treatment of resistant hypertension. Due to a reduction of whole body sympathetic activity, additional benefits on cardiac adaptation have been proposed. The purpose of this study was to investigate the effect of RDN on blood pressure (BP) as well as cardiac mass and function via cardiac magnetic resonance imaging (CMRI).RDN was performed on 15 patients with a history of resistant hypertension . Office and ambulatory long term blood pressures were measured before and 12 months after RDN. For quantitative CMRI, an electrocardiographically triggered steady-state free precession (SSFP) cine sequence  was performed in short- and long-axis views before and 12 months after RDN. Quantitative analysis included end-diastolic (EDV) and end-systolic volumes (ESV), stroke volume (SV), left ventricular ejection-fraction (EF) as well as end-diastolic (EDMM) and end-systolic myocardial mass (ESMM). CMRI data were analyzed by two independent observers using the HeAT-Software. Data are given as the mean of both observers. Statistical analysis was performed using GraphPad Prism 4 and Excel, Microsoft.In patients with resistant hypertension, RDN let to a significant decrease of EDMM  and ESMM  within 12 months after intervention. EDV (163.0 ± 38.6 ml vs 168.1 ± 49.8 ml), ESV (70.4 ± 33.0 ml vs 72.0 ± 39.8 ml), SV (92.7 ± 20.7 ml vs 96.1 ± 30.6 ml) and EF (0.583 ± 0.116% vs 0.588 ± 0.126%) did not change on a significant level. BP measurements revealed a significant decrease of the minimal diastolic BP in ambulatory long term measurements . No additional significant changes in average, systolic or diastolic, office or ambulatory, diurnal or nocturnal BP measurements was detected.RDN lead to a decrease of cardiac mass within 12 months after intervention without a significant change of left ventricular function. Additionally, minimal diastolic BP showed a significant decrease in ambulatory measurements, whereas no other significant changes in BP levels were detected. Despite a rather small effect on blood pressure, additional benefits of RDN regarding cardiac adaptation can be observed. Further investigations might lead to a specified selection of patients who benefit from RDN beyond reduction of BP.


Radiation therapy is an effective and broadly applied adjuvant in the treatment of many malignancies. Collateral radiation exposure to the heart can result in relevant cardiac disease, which might not be manifest until years after treatment. Aim of this study was to test whether cardiovascular magnetic resonance (CMR) identifies signs of early cardiac injury.We prospectively applied CMR at 1.5T before (a), at half-time (b) and after radiation therapy (c) in patients with different thoracic malignancies. Besides SSFP-based cine imaging for cardiac morphology and function, we performed pre- and post-contrast T1-mapping (MOLLI) as well as late gadolinium enhancement (LGE) imaging for tissue characterization. T1-times were assessed in a mid-ventricular short axis. LV Ejection Fraction (LVEF) and the partition coefficient λ were calculated.Ten patients  were included. One patient was excluded due to an unknown metallic implant, one declined at baseline, one at half-time and one at after radiation therapy examination. Mean heart dose was 11.5 ± 9.6Gy. LVEF of all patients was above 50% at baseline. It dropped below 50% in one patient at half-time and in two patients at after radiation examination (Figure The incidence of pericardial effusion increased during radiation therapy, while CMR tissue analysis failed to identify early myocardial injury in this small number of patients. The LVEF changed in some individuals. A larger trail and subgroup analysis is needed for further differentiation.