The restrictive cardiomyopathies constitute a heterogeneous group of myocardial diseases with a different pathogenesis and overlapping clinical presentations. Diagnosing them frequently poses a challenge. Echocardiography, electrocardiograms and laboratory tests may show non-specific changes. In this context, cardiac magnetic resonance (CMR) may play a crucial role in defining the diagnosis and guiding treatments, by offering a robust myocardial characterization based on the inherent magnetic properties of abnormal tissues, thus limiting the use of endomyocardial biopsy. In this review article, we explore the role of CMR in the assessment of a wide range of myocardial diseases causing restrictive patterns, from iron overload to cardiac amyloidosis, endomyocardial fibrosis or radiation-induced heart disease. Here, we emphasize the incremental value of novel relaxometric techniques such as T1 and T2 mapping, which may recognize different storage diseases based on the intrinsic magnetic properties of the accumulating metabolites, with or without the use of gadolinium-based contrast agents. We illustrate the importance of these CMR techniques and their great support when contrast media administration is contraindicated. Finally, we describe the useful role of cardiac computed tomography for diagnosis and management of restrictive cardiomyopathies when CMR is contraindicated. Restrictive cardiomyopathy (RCM) is a myocardial disorder that is usually caused by increased myocardial stiffness which results in impaired ventricular filling. Until later stages of the disease, biventricular chamber size and systolic function are usually normal or almost normal. RCM include primary or idiopathic  and secondary forms, which include infiltrative, non-infiltrative and storage disorders.RCMs are generally caused by processes causing abnormal deposition of proteins, glycogen and iron within the myocardium, leading to ventricular stiffness with diastolic dysfunction.Non-infiltrative: idiopathic RCM, scleroderma, pseudoxanthoma elasticum;Infiltrative: amyloidosis, sarcoidosis, Gaucher’s, Hurler’s;Storage diseases: Anderson–Fabry disease (AFD), glycogen storage, hemochromatosis and iron overloadEndomyocardial: endomyocardial fibrosis (EMF), radiation-induced, drugs, carcinoid, metastatic tumor.The most common classification system  in adultThe most common initial clinical manifestations are exertional dyspnea, exercise intolerance due to inability of the ventricular filling, fatigue and lower extremity edema, whereas heart failure symptoms occur only in advanced stage; atrial enlargement can lead to arrhythmias and concomitant thromboembolic complications are not uncommon .Transthoracic echocardiography (TTE) is the first-line examination. The most common TEE findings are its normal right and left systolic function until advanced stage , normal or reduced left ventricular (LV) volume and bi-atrial enlargement, with abnormal diastolic compliance characterized by increased early diastolic filling velocity due to elevated left atrial pressure.Wall thickness is generally normal, except for infiltrative and storage processes in which case it is typically increased.Cardiovascular magnetic resonance (CMR) can combine the morphologic and functional evaluation with an accurate characterization of the myocardial changes on the basis of the intrinsic magnetic properties of different tissues . Moreover, the use of gadolinium-based contrast agents (GBCA) may improve the evaluation of myocardial damage based on late gadolinium enhancement (LGE) technique and post-contrast T1 mapping sequences, which permit to calculate extracellular volume (ECV) . The. The4]. As they are currently available by all vendors, T1 and T2 mapping techniques should be used to characterize in a quantitative and reproducible way the tissue signal alterations in ICM and RCM , 5. NatiFinally, in case of suspected iron overload cardiomyopathy (IOC)-specific gradient echo sequences designed to measure T2* relaxation time should be incorporated into the CMR protocol in order to detect the excessive myocardial iron deposition (see specific section).Main CMR features of RCM are summarized in Table Amyloidosis is a group of diseases caused by protein misfolding resulting in aggregation and deposition of amyloid fibrils . CardiacMore than 30 proteins are known to cause amyloidosis, and two types are predominantly responsible for cardiac involvement: immunoglobulin light chain amyloid (AL) and transthyretin amyloid (ATTR). ATTR amyloidosis is divided into a hereditary form associated with mutations of TTR protein (ATTRm), and a more common non-hereditary wild-type form (ATTRwt), a late-onset disease affecting predominantly men. ATTRwt almost exclusively affects the heart, while ATTRm has a wide range of presentations .AL amyloidosis, the most frequent form of systemic amyloidosis, has an estimated prevalence of 8–12 cases per million person-years, and cardiac involvement occurs in 50–75% of cases . CA is cThe reference standard for the diagnosis of CA is endomyocardial biopsy, an invasive procedure not widely available. In addition, the biopsy sample may not be representative of the infiltration status of the whole myocardium. Imaging offers a noninvasive alternative to evaluate the whole heart .As CA is an important predictor of poor outcome, early diagnosis is crucial in both AL and ATTR amyloidosis. Imaging may guide the selection and the dosage of the chemotherapy to minimize treatment-related exacerbation of heart failure. In particular, CMR seems a promising tool to track different disease mechanisms  and to evaluate cardiac involvement progression or regression during the course of the therapy . The ideCMR is a useful tool to differentiate the diagnosis between CA and other conditions  . CA was The evaluation of ventricular morphology and function in CA should be performed with cine images obtained using SSFP sequences acquired in long axis and short axis planes covering the LV.LGE imaging with inversion recovery sequences is a fundamental technique to diagnose CA . LGE imaT1 mapping demonstrates an increased nT1 time in CA Fig.  and is rThe development of caseating granulomas and tissue scarring represent the typical features of sarcoidosis, a systemic inflammatory disease that involves multiple organs and apparatus with an US annual prevalence of 10.9−35.5/100.000 in African-Americans and a cardiac involvement in 25% of subclinical patients .A wide range of manifestations characterizes cardiac sarcoidosis (CS), the most common including complete heart block and right bundle branch block, ventricular arrhythmias and sudden cardiac death . DiagnosThe lysosomal storage disorders (LSD) and in particular the glycosphingolipidoses , glycogen storage diseases  and mucopolysaccharidosis frequently involve cardiac structures, causing infiltrative cardiomyopathies . In the AFD is an X-linked disease  , caused AFD often appears as concentric LV hypertrophy with a variable degree of myocardial wall thickening and papillary muscles prominence, which lately (?) may lead to arrhythmias, myocardial ischemia or heart failure . AFD usuOn TTE, AFD phenotype overlaps many other hypertrophic conditions; therefore, the diagnosis may be challenging when not supported by specific ECG signs, positive familiar history or other manifestations of AFD. CMR has rapidly gained a crucial role in the diagnostics, as it combines the assessment of cardiac function and the characterization of tissue abnormalities .LGE has been found in up to 50% of AFD patients ; usuallyAs validated in various studies –34, myocIn a study performed on 123 patients, nT1 distinguished AFD from hypertrophic cardiomyopathy (HCM) and healthy controls  using a cutoff value of 940 ms on a 1.5 T scanner and modified lock–locker inversion (MOLLI) recovery sequence, whereas a better diagnostic performance is obtained with 3.0T scanner  . MyocardIn a recent study, an increase in T2-weighted signal was found in 24/78 AFD patients reflecting myocardial edema, whereas myocardial inflammation was confirmed by histology in 44/78 patients . Other aAlthough systolic function assessed by ejection fraction is generally normal in AFD patients, different studies reported myocardial strain reduction assessed with feature tracking (FT) technique. In particular, AFD patients show impairment in global longitudinal strain (GLS) correlated with myocardial damage degree (presence of LGE and cardiac biomarkers) and nT1 values, even at pre-hypertrophic stage . FurtherFinally, the role of CMR to assess the response to ERT is under investigation. It has been found that ERT induces a decrease in myocardial T2 values, and in LV mass and wall thickness of patients with little or no LGE at baseline . ERT alsIron overload or hemochromatosis indicates accumulation of iron in the body due to genetic metabolic disorders with increased intestinal iron absorption (primary form) or repeated blood transfusions (secondary form) . When inMyocardial iron overload is a progressive process depending on the increasing levels of serum iron, regulated through transferring mediated uptake mechanisms. In the cardiomyocytes, iron deposition initially occurs in the perinuclear lysosomes, but when the overload exceeds, iron can accumulate throughout the sarcoplasm , 41.Myocardial iron deposition initially begins within the epicardium and then extends toward the endocardium, which helps explain the preservation of systolic function until very late in the disease. The excess of iron may be removed with chelation therapy, even though the reversibility of myocardial damage is reduced in the more advanced stages of the disease .Clinical presentation of IOC varies from the total absence of any symptoms or only exertional dyspnea at early phase to heart failure symptoms, when the damage severely affects LV systolic function and determines dilated cardiomyopathy . Right hTTE is commonly used to screen the patients and for clinical follow-up. It is able to detect abnormalities in terms of wall thickness or myocardial contraction, but it may not directly visualize tissue iron deposition . At TTE,CMR has emerged as the best noninvasive method to quantitatively assess the myocardial iron load , 42. In In particular, iron deposits create a rapid signal loss with increasing echo time that can be better assessed as a reduction in T2* time, calculated with an exponential function using a multiecho gradient echo sequence . T2* meaA value of 20 ms is considered the best performing threshold to define myocardial siderosis at 1.5T scanner . MyocardT2* value ranging from 10 ms to 20 ms at 1.5T (from 5.5 ms to 12 ms at 3.0T) is highly indicative of moderate myocardial siderosis and it is correlated with LV ejection fraction , and T2*T2* relaxation time is not correlated with serum ferritin levels, although there is a strong correlation with the quantified amount of iron deposition from myocardial biopsy . T2* imaAlthough the T2* technique remains the reference technique for clinical assessment of iron overload, great advantages are offered by the novel T1 and T2 mapping sequences, since myocardial values are reduced in both sequences .In addition, in patients with only mild increases in cardiac iron, nT1 showed a superior reproducibility as compared to T2* measurements (about 2.5–7 fold T2*) .LGE was also detected in the 15,6–19% of patients with Thalassemia Major and the extent of myocardial fibrosis was comparable in patients that developed heart failure and patients who did not .Finally, ECV may be increased in patients with cardiac iron overload, as it reflects diffuse interstitial myocardial fibrosis that occurs in more advanced phases of the disease .EMF is characterized by deposition of fibrous tissue in the endocardium leading to restrictive pattern, with the reduction in ventricular volumes and increase in atrial volumes, normal wall thickness or apical obliteration due to fibrous endocardial thickening .EMF was initially described in tropical countries, in young adults with a bimodal distribution peaking at 10 and 30 years of age, mainly in rural and poor populations .Although the pathogenesis is unclear, malnutrition, parasitic infestation , genetic factors have been proposed as potential causes triggering inflammation and immunomodulation. Hypereosinophilia, infection disease and autoimmunity may act as a profibrotic role by promoting the synthesis of collagen by fibroblasts, with progressive endomyocardial damage and scarring.EMF usually starts with active diffuse inflammation with endothelial damage, myocardial edema, eosinophilic infiltration and subendocardial necrosis and vasculitis, frequently associated with pericardial effusion and thrombi adherent to endocardial surfaces. When the inflammatory activity declines, it evolves in a progressive interstitial fibrosis and myocyte hypertrophy (chronic phase) causing RCM, whose phenotype is characterized by biventricular volume reduction and atrial dilatation, and subsequent isolated right-sided heart involvement with apical retraction.Extensive EMF may cause restrictive patterns, apex obliteration  and diastolic dysfunction.CMR offers a comprehensive evaluation of ventricular function and morphology , endocavitary thrombus detection and assessment of tissue abnormalities.LGE typically involves the endocardial and subendocardial layers of both ventricles; with a non-coronary pattern, and the subvalvular apparatus and chord, LGE is typically a continuous hyperintense stria extending from the subvalvular region to the apex, where it is usually more prominent Fig.  50].Fig.Fig50].FIn this setting, CMR has a role not only for diagnosis and staging, but also in assessing response to treatment, in inhibiting inflammation and solving thrombosis, and in prognostic stratification .Radiation therapy is a valuable therapeutic option, which improves clinical outcome and reduces post-surgery recurrences in various thoracic malignancies . Among potential complications, cardiovascular diseases are among the most serious and for a long time were underestimated.The term “radiation-induced heart disease” (RHD) depicts a complex entity that can manifest in a large number of conditions, such as accelerated atherosclerosis, valve disease, cardiomyopathies, conduction system abnormalities and pericarditis . RHD is A spectrum of different phenotypes are associated with RHD, including myocardial fibrosis with wall motion anomalies, LV hypertrophy, diastolic dysfunction with restrictive phenotype and congestive heart failure, and are quite common in patients who received more than 60 Gy or chemoradiotherapy .In this clinical setting, the role of CMR for the assessment of RHD has not been fully established.CMR appears promising in anticipating the RHD diagnosis by depicting the early myocardial tissue changes related to the radiation-induced damage before the occurrence of functional impairment, with consequent impact in patient management and treatment strategy .Very few studies investigated RHD using CMR. Umezawa et al.  found LGThe quantitative biventricular functional assessment offered by cine sequences is recommended in those with suboptimal TTE or discrepant results on 2016 ESC Position Paper on Cancer Treatments and Cardiovascular Toxicity . PericarNovel T1 and T2 mapping techniques could open new perspectives in the early detection of diffuse myocardial inflammation and fibrosis following RHT. However, systematic studies are still lacking and preliminary experiences have been reported only as isolated case reports .The distinction between constrictive pericarditis (CP) and RCMs could be challenging, as the two manifest with overlapping clinical presentations and restrictive flow patterns with diastolic dysfunction at TTE .RCMs are associated with increased stiffness and reduced relaxation of ventricular walls, which alter the elastic properties or the extracellular matrix of the myocardial tissue.Conversely, CP is typically a complication of chronic pericarditis or pericardiotomy and determines an encasement of cardiac chambers in a rigid pericardial sac, resulting in interventricular dependence and dissociation between intracardiac and intrathoracic pressures during respiration .CMR provides useful information that helps to differentiate the diagnosis between CP and RCMs.black blood” T1-weighted sequences and cine-SSFP can demonstrate a diffuse thickening of pericardial layers with calcifications  , wh, wh64], According to Power et al., tagged cine-MRI enabled the assessment of adherences between visceral and pericardial layers of pericardium by identifying the absence of slippage, with a sensitivity and diagnostic accuracy of 100% .Cardiac computed tomography angiography (CCTA) has a role for disease characterization in patients with suspected RCM with contraindication to CMR , as well as to exclude coronary artery disease.Retrospective ECG-gated CCTA scan with multiphase reconstruction may assess ventricular wall thickness, shape and volumes, with excellent correlation to both TTE and CMR . CCT canLGE is the cornerstone of differential diagnosis of cardiomyopathies in CMR and can be demonstrated also with CCT . The latAlthough LIE can be demonstrated with single energy scanners , dual enECV has been demonstrated to be a robust indicator of disease burden and a prognostic marker in CA and its results are altered in other ICM . ECV canThe advantages of CCT imaging consists in wide scanner availability, reduced costs and examination time, simultaneous evaluation of the coronary arteries and the possibility to perform in patients with CMR contraindications. Disadvantages are a less robust tissue characterization compared with CMR and the patient exposure to ionizing radiations and iodinated contrast medium.CMR is emerging as a robust and powerful noninvasive imaging modality for the diagnosis of various forms of ICMs and RCMs. The myocardial tissue characterization offered by CMR and strengthened by the novel T1 e T2 mapping technique, may identify those storage or infiltrative forms that are associated with characteristic alterations of the myocardial relaxometric properties or detect other restrictive conditions, where myocardium is subject to diffuse inflammation or fibrosis. When the clinical scenario is unclear, a CMR multiparametric approach may help to reach the correct diagnosis with a significant impact on clinical decision making.


Rats were examined at five or eight weeks with right-heart catheter, cardiac magnetic resonance, and autopsy. Compared to normoxic controls (23.9 ± 4.1 mmHg), right ventricular systolic pressure was elevated in Sugen–hypoxia rats at five and eight weeks . Right ventricular end-systolic volume index was increased in eight weeks Sugen–hypoxia  compared to normoxic controls (0.18 ±0.03 mlcm–2). There was progressive dilatation of the right ventricular at eight weeks Sugen–hypoxia compared to normoxic controls (0.75 ± 0.13 µlcm–2 vs 0.56 ± 0.1 µlcm–2p = 0.02). Ventricle mass index by cardiac magnetic resonance at five weeks  and eight weeks Sugen–hypoxia  were higher than normoxic controls (0.21 ± 0.04). Stroke volume, right ventricular ejection fraction, and left ventricular variables were preserved in Sugen–hypoxia. Ventricular changes during the course of illness in a pulmonary arterial hypertension rodent model can be examined by cardiac magnetic resonance. These changes including right ventricular hypertrophy and subsequent dilatation are similar to those seen in pulmonary arterial hypertension patients. Despite the persisting pulmonary hypertension, there are features of adaptive cardiac remodeling through the study duration.Cardiac magnetic resonance-derived ventricular variables are predictive of mortality in pulmonary arterial hypertension. Rodent models which emphasize ventricular function, allowing serial monitoring, are needed to identify pathophysiological features and novel therapies for pulmonary arterial hypertension. We investigated longitudinal changes in the Sugen–hypoxia model during disease progression. Sprague Dawley rats ( Stroke volume,2 RV ejection fraction,3 and RV and LV end-diastolic volume (EDV)4 have all shown to be prognostic markers in PAH patients.Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature; however, it is subsequent right ventricular (RV) failure that is the main cause of morbidity and mortality in patients. Cardiac magnetic resonance (CMR) is a non-invasive imaging tool providing high-resolution three-dimensional images of the heart. During CMR, ventricular short axis stacks are used to reconstruct a 3D image of the right and the left ventricle (LV), and ventricular volumes, mass, and function can be measured.Small animal (rodent) models are increasingly used to identify pathophysiology as well as therapies for PAH with the intention of translating findings to humans. Accurate monitoring of disease in rodents with emphasis on ventricular function  without killing the animal is needed.5 A combination of Sugen and chronic hypoxia cause pulmonary endothelial cell death and severe PH. Subsequently in 2010, Abe et al. showed that SuHx rats demonstrated evidence of severe pulmonary arteriopathy including concentric neo-intimal and complex plexiform-like lesions which closely resemble plexiform lesions seen in humans.6 Subsequently, other groups have attempted to characterize hemodynamics in a SuHx model beyond right heart catheterization alone. Vitali et al. evaluated longitudinal changes in a SuHx mouse model of PH. Echocardiographic and invasive measurements were performed after three weeks of hypoxia and after 10 weeks of recovery in normoxia. Ten weeks after hypoxic exposure, RV systolic pressure (RVSP) had decreased, but remained elevated compared to normoxic controls. However, RV hypertrophy had resolved. They observed very few angio-obliterative lesions at 10 weeks.7 De Raaf et al. used telemetry to characterize hemodynamics in SuHx rats and associated these with serial histology.8 Jones et al. demonstrated a good correlation between M-mode and Doppler Echo vs right heart catheterization in the monocrotaline rat model.9 In a study by Urboniene et al. assessing validation of high resolution echocardiography and CMR vs high fidelity catheterization in experimental PH monocrotaline rat model, non-invasive measures of RV free wall thickness/mass correlated well with post mortem measurements.10Various rodent models to recapitulate human PAH have been produced. Sugen-5416 (Sugen), an inhibitor of vascular endothelial growth factor was shown to cause a mild rise in pulmonary artery pressure in wild-type rats. Combining Sugen with another stimulus of pulmonary hypertension (PH), i.e. chronic hypoxia, Taraseviciene-Stewart et al. described the Sugen–hypoxia (SuHx) rat model in 2001.12 The same non-invasive and repeatable measurements would be of great advantage for the study of rodent models to allow a detailed understanding of ventricular structural and functional changes that occur, to enhance efficacy in translational medicine. We investigated whether CMR is feasible in a SuHx rat model of PH. Subsequently, we investigated the structural and functional changes associated with the model during disease progression. Finally, we discussed the suitability of the SuHx model for translational studies of the mechanisms of RV dysfunction in PAH.Our group has a proven track record using CMR imaging to evaluate RV function in humans with PAH.All experimental procedures were carried out in accordance with the United Kingdom Animal Procedures Act (1986) and with the US NIH publication No. 85-23, revised 1996, and ethical approval was also granted by the University of Glasgow Ethics Committee. Rodents were housed in a 12-h light–dark cycle with access to food and water ad libitum.n = 32) were divided into two groups (n = 16 in each group). Group 1: SuHx—a single dose of subcutaneous Sugen-5416  suspended in vehicle (20 mg/kg), before being placed in a hypobaric chamber (atmospheric pressure 550 mbar) for two weeks and then placed in normal room pressure (1013 mbar) for three weeks whilst PH developed. Group 2: Normoxia—maintained at normal room pressure for five weeks. In each group (n = 16), half the animals entered the CMR arm of the study (n = 8) while the other half underwent right heart catheterization for hemodynamic assessment (n = 8). Animals were assessed at five weeks and eight weeks from the beginning of the study. The study design is summarized in Male Sprague Dawley rats (three weeks)  isoflurane and then maintained at 2% (v/v) isoflurane supplemented with a constant flow of 5% (v/v) oxygen. Hemodynamic measurements were taken using an ultra-miniature Polyimide Nylon catheter capable of measuring ventricular pressure continuously . The catheter was used as per the manufacturer’s instructions with the PowerLab 35 Series data acquisition system with LabChart Pro and the pressure volume (PV) loop analysis module. For right heart pressure analysis, the catheter was inserted into the jugular vein and guided into the RV to measure RVSP.Following hemodynamic assessment, animals were culled and hearts flushed with phosphate buffered saline using a blunt needle to clear peripheral blood cells. Euthanasia consisted of an overdose of anesthetic followed by a schedule 1 kill . The heart was isolated, atria removed, and tissue fixed with 10% (v/v) neutral buffered formalin for 48 h before paraffin processing for histological analysis by immunohistochemistry. Tissue was sectioned by microtome at width of 5 µm and stained by Gomori’s trichrome staining kit  as per manufacturer’s instructions.After the heart was isolated and atria removed, the RV and LV weights were obtained to determine RV hypertrophy. Interventricular septum was considered part of the LV.Vascular thickening was determined by smooth muscle actin antibody  staining, thickening was characterized by an increase in the vessel wall diameter of more than 50% of the arterial wall or complete occlusion. The number of remodeled vessels over the total number of vessels present in a lung section was determined. Sections were analyzed in a blinded manner.CMR imaging was performed in a Bruker Biospec 7-T/30-cm  system with a gradient coil insert (400 mT/m). Using a 72-mm transmit birdcage resonator and four channel phased array rat cardiac receiver coil. Anesthesia was induced with gas flow at 2–3 l/min, and the isoflurane delivered via a vaporizer  at 3–4%. The exhaust was connected to the Omnicon F/Air device (AM Bickford). After induction, animals were maintained at 2% (v/v) isoflurane supplemented with a constant flow of 5% (v/v) oxygen. An external water jacket was used to maintain a core temperature of 37℃. During all procedures, body temperature, ECG, and respiration were monitored . Long and short axis scout images were acquired so that short axis images could be planned using a segmented, cardiac-triggered FLASH sequence. The images were acquired with a slice thickness of 1.5 mm, ensuring the entire biventricular length is covered. The CMR parameters were as follows. Slice thickness—1.50 mm, field of view—30.00 mm × 30.00 mm, image matrix—192 × 192 pixels, image resolution—156 µm × 156 µm, Flip angle—15 degrees, Echo time—2.50 ms, Rep. time—7.02 ms, number of frames—25, number of averages—6, and software version—Paravision 5.1.13Scans were coded by number and analyzed in batches by G.J who was blinded to the identity and hemodynamic results at the time of analysis. A second observer (A.U) analyzed five scans for inter-rater agreement analysis. Trabeculations and papillary muscles were considered as part of the blood pool. The epicardial and endocardial borders were manually outlined in end-diastolic and end-systolic frames using QMass . Stroke volume was determined from EDV – end-systolic volume (ESV) of the LV. Ejection fraction ((SV/EDV) × 100%) was also determined. RV and LV masses were determined by manual planimetry at diastole. Ventricular mass index (VMI) was defined as the ratio between RV to LV mass, with the interventricular septum considered part of the LV. LV eccentricity index (LVEI) was defined as the ratio between maximum anterior–posterior to septal lateral diameters of the LV and was measured at both systole and diastole. All ventricular volumes and mass measurements were indexed to body surface area.–2 and mgcm–2, respectively, indexed for body surface area. Statistical analysis was performed using SPSS  and GraphPad Prism . A significance level of 0.05 was employed for statistical tests. An analysis of variance test was used to compare RV and LV mass, volumes, and function between normoxic animals and different stages of SuHx. If there was statistical significance, a Tukey test was used for post hoc analysis. To compare different methods of VMI measurement (CMR vs autopsy), a spearmen correlation was used. Inter-rater variability for determination of LV and RV function were calculated from paired measurements of the LV ejection fraction (LVEF) and RV ejection fraction (RVEF) of two readers as interclass correlation coefficient with a two-way mixed model for absolute agreement. Results are shown as mean ± SD unless otherwise stated.Ventricular volumes and mass are given as µlcmp = 0.03; 48.89 ± 9.6 mmHg, p = 0.002, respectively). There were no significant differences in RVSP between SuHx rats at five and eight weeks. Similarly, relative RV mass measured at autopsy by RV/(LV + septum) was significantly elevated at five weeks  and eight weeks  SuHx compared to controls (0.25 ± 0.04) , there was no significant difference observed between SuHx rats at five and eight weeks (Compared to normoxic rats (23.87 ± 4.1 mmHg), RVSP was significantly elevated in SuHx rats at both five and eight weeks  . Immunohht weeks .Fig. 2.A representative long axis image (a) and a short axis cine stack (b) to (f) are shown in There was excellent agreement between the two observers  for LVEF as well as for RVEF .p = 0.003) compared to normoxic rats (0.18 ± 0.03). There were no significant differences between normoxia and SuHx at five weeks. Compared to normoxic rats (0.17 ± 0.03), RV mass index was increased in the SuHx rats at five weeks  and eight weeks . RV demonstrated progressive dilatation (increasing RVEDV index) at eight weeks of SuHx compared to normoxic rats . In RVEF, there were no significant differences between normoxic rats and five and eight week SuHx rats; however, demonstrating trends toward impairment . Stroke volume index was preserved in the SuHx model at five and eight weeks compared to normoxia (0.44 ± 0.1 vs 0.5 ± 0.04 vs 0.49 ± 0.1). VMI after five weeks  and eight weeks of SuHx  were significantly higher than normoxic rats (0.21 ± 0.04)  .Fig. 4.No differences were observed between the normoxic and SuHx groups  in terms of LVEDV index (0.73 ± 0.08 vs 0.74 ± 0.06 vs 0.75 ± 0.16), LVESV index (0.29 ± 0.05 vs 0.24 ± 0.04 vs 0.25 ± 0.03), LV mass index (0.79 ± 0.07 vs 0.82 ± 0.09 vs 0.8 ± 0.15), or LVEF (60.3 ± 7.03 vs 67.8 ±3.16 vs 66.5 ± 3.12) .Fig. 5.p = 0.006) and in SuHx rats at eight weeks  compared to normoxic rats (0.98 ± 0.08). There were no differences between LVEI at diastole between normoxia and SuHx at five or eight weeks (1.06 ± 0.05 vs 1.14 ± 0.04 vs 1.1 ± 0.06)  .Supplementary file demonstrates CMR variables between normoxia and Sugen hypoxia at five and eight weeks.r = 0.8328, 95% CI: 0.5633–0.9422, p < 0.0001). However, MR images demonstrate functional aspects of RV contraction including septal flattening and paradoxical septal motion during systole due to RV pressure overload.CMR images taken from a normoxic and SuHx animals and light microscopy images of the same animals at autopsy were compared. Although both techniques could visually demonstrate ventricular size and wall thickness (hypertrophy), CMR demonstrated functional aspects of RV contraction including septal flattening and paradoxical septal motion during systole in SuHx animals. 7 Previous CMR studies used phase contrast imaging but did not explore LV and RV volume and functional variables known to be prognostic in PH, nor look at longitudinal changes.10To the best of our knowledge, this is the first study demonstrating longitudinal biventricular mass, volume, and function in a PH animal model using CMR. Previous studies had used echocardiography to examine biventricular function and structure in small animal models of PAH.Our study demonstrated the feasibility of CMR in a small animal model of PAH with good spatial and temporal resolution and excellent inter-observer reproducibility. The future advantage of CMR over cardiac catheterization and autopsy is the ability to perform imaging serially on the same animal to look at disease progression and response to treatment without killing the animal.3 Although traditionally right heart catheterization and post mortem studies have been used, there is a need for non-invasive tests of RV function in animal models of PAH. In addition, we need to have a better understanding of the longitudinal changes in ventricular function in animal models of PAH. Although the RV is the obvious focus of attention, LV dysfunction can occur through cardiac interaction, thus simultaneous evaluation of the LV is important. Echocardiography is widely available and can be used to estimate RVSP; however, imaging of the RV with its complex geometry is difficult.The main cause of morbidity and mortality in patients with PAH is RV failure. It had been assumed that the cause of RV dysfunction was alterations to the pulmonary vasculature and therefore treatment focus had been centered on improving pulmonary hemodynamics, with the assumption that improvement in RV would follow. However, it is now evident that cardiac response to a given level of pulmonary hemodynamic overload is variable but important in the subsequent prognosis of these patients.14 The study demonstrated similar hemodynamics and RV hypertrophy compared to our study population after eight weeks. Abe et al. investigated the longitudinal hemodynamic and histological changes in the model. At 13–14 weeks after Sugen, the rats had very high RVSP (96 ± 11 vs 21) and severe RV hypertrophy .6 The varying degrees of RVSP and RV hypertrophy in these studies is likely related to the duration of exposure to hypoxia, however, could also be related to the animal strain, gender, and age at exposure.Plexiform lesions in the pulmonary vasculature are known to be the hallmark of PAH and attempts have been made to establish an animal model that closely mimics human disease. The SuHx model has been shown to cause severe PH with the development of plexiform lesions. We used a SuHx model consisting of an injection of Sugen, two weeks of hypobaric hypoxia and three weeks or normoxia. Dean et al. explored the effects of Metformin on the development of PH via aromatase inhibition, a similar SuHx model was used (Sugen + two weeks of hypobaric hypoxia and three weeks of normoxia).15 In our study, RV hypertrophy was followed by subsequent dilatation. However, stroke volume and RVEF were relatively preserved. This was despite the presence of persistently elevated RVSP. We believe this study represents the natural history of RV hypertrophy and failure, demonstrating compensated RV hypertrophy (adaptive remodeling) before progression into maladaptive remodeling with further RV dilatation and RV failure, with reduction of RV output.In humans with PAH, progressive narrowing of the pulmonary vasculature causes increased load to the RV. The RV adaptation results in increasing wall thickness (hypertrophy) and contractility (coupling). Ventriculo–arterial coupling preserves stroke volume and ventricular efficiency. The RV then dilates, increasing wall stress and oxygen consumption per gram resulting in uncoupling and reduced stroke volume.16 hypothesized that a SuHx mouse model may capture the transition from adaptive to maladaptive RV remodeling including impairment in RV function by studying PV measurements in vivo. The results suggested that RV remodeling may begin to shift from adaptive to maladaptive with increasing duration of SuHx exposure. However, for the duration of SuHx exposure used in their study, no drop in cardiac output was observed.16 We believe that our study demonstrates a period of adaptive remodeling of the RV with compensated hypertrophy with minimal RV dilatation at later stages of the study. By lengthening the exposure to SuHx, we may be able to identify the transition from adaptive to maladaptive remodeling and identify decompensated right heart failure in this model. Most patients present to clinical assessment when there are signs of more severe RV dysfunction and in contrast pre-clinical SuHx model demonstrate adaptive remodeling at least early in its disease progression. This is of importance in the design of pre-clinical studies as intervention with experimental therapeutics is likely to occur at this early adaptive stage of disease progression where RV function/stroke volume seem to be preserved despite the presence of PAH.Wang et al.18 Previous human studies have demonstrated that patients with progressive illness demonstrated lower LV systolic function compared to stable patients. Previous echocardiography studies have also demonstrated impaired LV strain and torsion in PAH patients.17 We observed preserved LV systolic function with preserved LV mass and volume variables in this small animal model of PAH. Although PAH animals demonstrated paradoxical septal motion of the septum in our study, preserved RV output probably explains the preserved LV function.In PAH, impaired LV performance is explained by low RV cardiac output and direct ventricular interaction due to inter-ventricular dyssynchrony and paradoxical septal motion.CMR is feasible in a small animal model of PAH and could be used in pre-clinical animal studies to explore bi-ventricular structural and functional changes during the course of illness. It is likely that the SuHx model demonstrates adaptive remodeling to persistently elevated pulmonary pressures which is demonstrable by preserved RV function and stroke volume with hypertrophy of the RV. Further longitudinal studies are required to assess this model in detail, especially focusing on longitudinal RV response. The search for better animal models of PH continues because our understanding of the pathobiology of disease and the development of new therapeutic strategies depends on robust animal models, but at present, no single model has all the features of human disease.19 Future studies with late gadolinium enhancement data will provide further insights into myocardial remodeling in PAH.The study assessed rats at five and eight weeks from Sugen exposure, while assessment later may have demonstrated worsened hemodynamics and RV variables mimicking disease presentation in humans. The rats were anesthetized with isoflurane, previous studies using halogenated anesthetics have been shown to impair RV–PA coupling; however, these effects were seen both in hypoxia and hyperoxia.Click here for additional data file.Supplemental material, PUL897513 Supplemental material for Understanding longitudinal biventricular structural and functional changes in a pulmonary hypertension Sugen–hypoxia rat model by cardiac magnetic resonance imaging by Geeshath Jayasekera, Kathryn S. Wilson, Hanna Buist, Rosemary Woodward, Aysel Uckan, Colin Hughes, Margaret Nilsen, A Colin Church, Martin K. Johnson, Lindsay Gallagher, James Mullin, Mandy R. MacLean, William M. Holmes, Andrew J. Peacock and David J. Welsh in Pulmonary Circulation


ECV was then used to estimate TCVCMR at LVmyo and LVseptum following previously published formulas. Tissues were prepared following an established protocol and stained with picrosirius red to analyze the TCVhisto in LVmyo and LVseptum. TCV measured at LVmyo and LVseptum with both histology  and T1-Mapping  did not show any regional differences. TCVhisto and TCVCMR showed a good level of data agreement by Bland–Altman analysis. Estimation of TCV through CMR may be a promising way to non-invasively assess myocardial collagen content and may be useful to track disease progression or treatment response.Right ventricular biopsy represents the gold standard for the assessment of myocardial fibrosis and collagen content. This invasive technique, however, is accompanied by perioperative complications and poor reproducibility. Extracellular volume (ECV) measured through cardiovascular magnetic resonance (CMR) has emerged as a valid surrogate method to assess fibrosis non-invasively. Nonetheless, ECV provides an overestimation of collagen concentration since it also considers interstitial space. Our study aims to investigate the feasibility of estimating total collagen volume (TCV) through CMR by comparing it with the TCV measured at histology. Seven healthy Landrace pigs were acutely instrumented closed-chest and transported to the MRI facility for measurements. For each protocol, CMR imaging at 3T was acquired. MEDIS software was used to analyze T1 mapping and ECV for both the left ventricular myocardium (LV One of the most interesting features of magnetic resonance imaging (MRI) is the sensitivity to tissue composition, reflecting the physiologic and the pathophysiologic states. The T1 relaxation time, which is defined as a measure of how fast the nuclear spin magnetization returns to its equilibrium state after a radiofrequency pulse in the MRI scanner, not only contributes to the soft tissue contrast in MRI, but is also a direct marker of the chemical environment of the individual spins . By compWhile T1 mapping and ECV are established techniques for the evaluation of fibrosis in clinical practice , 7, someThe experimental protocols were approved by the local bioethics committee of Berlin, Germany (G0138/17), and conform to the “European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes” .2 of 0.5, an I:E-ratio of 1:1.5, the positive end-expiratory pressure was set at 5 mmHg and the tidal volume (VT) at 10 ml kg−1. The respiratory rate was adjusted constantly to maintain an end-expiratory carbon dioxide partial pressure between 35 and 45 mmHg. Under fluoroscopic guidance all animals were instrumented with a Swan-Ganz catheter . After the experiment, the pigs were sacrificed with an intracoronary 80 mmol potassium bolus. The myocardium was explanted and put in a formalin solution for fixation.Briefly, healthy Landrace pigs  were fasted overnight with free access to water, sedated and intubated on the day of the experiment. Anaesthesia was continued with isoflurane, fentanyl, midazolam, ketamine and pancuronium. Pigs were ventilated  with a FiO3 and 40 phases per cardiac cycle.All CMR images were acquired in a supine position using a 3T  MRI scanner with an anterior and the built-in posterior coil element, where up to 30 coil elements were employed, depending on the respective anatomy. All the animals were scanned using an identical comprehensive imaging protocol. The study protocol included initial scouts to determine cardiac imaging planes. Cine images were acquired using an ECG-gated balanced steady state free precession (bSSFP) sequence in three LV long-axis  planes. The ventricular two-chamber and four-chamber planes were used to plan a stack of short-axis slices covering entire LV. The following imaging parameters were used: Repetition time (TR) = 2.9 ms, echo time (TE) = 1.45 ms, flip angle = 45°, voxel size = 1.9 × 1.9 × 8.0 mm3, TR/TE = 3.3/1.6 ms, and flip angle = 15°. Inversion time to null the signal of healthy myocardium was assessed individually with the use of a Look-Locker-Sequence. Short-axis late gadolinium enhancement (LGE) views of the entire LV myocardium and 2-, 3-, and 4-chamber LGE views were obtained.Late gadolinium enhancement images were acquired 10 to 15 min after bolus injection of 0.2 mmol/kg gadobutrol  with an inversion-recovery 3-dimensional spoiled gradient echo sequence. Typical parameters were voxel size = 1.7 × 1.7 × 5 mm3, reconstructed voxel size 1.0 × 1.0 × 10 mm3, slice thickness 10 mm, TR/TE = 2.8/1.4 ms, flip angle 20°, parallel acquisition SENSE = 2, acquisition in end-diastole.For diffuse fibrosis assessment, we acquired a single breath-hold modified Look-Locker inversion-recovery (MOLLI) sequence  in a basmyo) and in the LV septum (LVseptum), two different regions of interest were drawn in the myocardium and in the septum for basal and medial slices (pre-contrast and post-contrast T1 maps), with care taken to exclude the interface between myocardium and bordering structures (e.g. blood) to avoid partial volume effects . Endocardial and epicardial borders were drawn in all short-axis slices at end-diastole and end-systole to calculate the global myocardial volume, myocardial mass and LV ejection fraction by using the disc summation method . To calcOther regions of interest were drawn in the skeletal muscle and in the RV, but they were excluded from the analysis due to poor image resolution.myo refers to the myocardial and blood to the blood pool T1 relaxation times, and pre and post to the measurement before and after contrast administration, respectively. For all T1 values, the averages of the basal and medial values were used.ECV was calculated as previously described :\documenmyo and LVseptum [Finally, we quantified the absolute volume of the extracellular myocardial space (absolute ECV) in each patient by using the following formula for both LVLVseptum :\documenmyo volume) represents the global LV volume expressed in millilitres and is calculated as:LV myocardial volume  expressed as follows:myo, without septum), left ventricular septum (LVseptum) and right ventricular free wall . HE-stained slides were analyzed qualitatively by a board-certified veterinary pathologist for morphologic abnormalities. In addition, all picrosirius red-stained slides were digitized at 20× magnification using an Aperio CS2  slide scanner. The red-stained collagen content was determined by a software algorithm . These whole slides images were analyzed for the quantitative proportion of collagen fibers in the tissue specimen of the different anatomic locations. The histology protocol and the number of samples used are summarized in Fig. Whole hearts were fixed in formalin for at least 48 h and consecutively cut in approximately 1 cm thick transversal sections separating them in basal, medial and apical levels Fig. . All sec in g/ml .Fig. 2Ret test or Mann–Whitney test were performed, accordingly, to compare the two different techniques in the same group. The level of agreement between histology and T1 mapping was evaluated with Bland–Altman analysis. The correlations between histological parameters were assessed by linear regression analysis. A p-value < 0.05 was considered significant. The software Sigmastat  and SPSS  were used for statistical analysis and results display.All data are presented as mean ± standard deviation (SD). The presence of outliers was evaluated with Grubbs' test and when present they were opportunely removed. The normality of the data was assessed with the Kolmogorov–Smirnov test. Difference between groups at histology and CMR was analysed by one-way ANOVA. Paired student myo  and LVseptum  respectively. A significant difference was observed between T1 native measurements between LVmyo and LVseptum . No significant difference was observed between LVmyo and LVseptum either for T1 post and ECV.All the CMR parameters analysed through T1 mapping are represented in Table CMR was observed between LVmyo and LVseptum measured with T1 mapping  and LVseptum .The MRI measured LV mass measured was 85 g ± 19 while the LV myocardial volume was 81 ml ± 18. No difference in TCVgy Table . A compamyo) and left ventricular septum (LVseptum) with both T1 mapping and histological assessments in healthy Landrace pigs.Cardiovascular magnetic resonance (CMR) T1 mapping has emerged as a promising technique to detect myocardial scars, focal and diffuse fibrosis in different cardiomyopathies and even in patients with acute chest pain syndromes . HoweverIn our study, we have used volumetric shimming including a second order shim in a local volume around the heart, in order to keep the volumes of interest well within the region without banding artifacts. It has indeed been shown that significant errors in T1 may result already at relatively small off-resonance frequencies . HoweverTo compare the TCV measured with histology against CMR T1 mapping different approaches have been used. Bull et al.  and Messmyo volume, which includes both the myocardium mass and density measured with MRI as already described in a previous study by our group [mass measured with MRI. By then comparing the corrected TCV of both T1 mapping and histology no differences were found for both LVmyo and LVseptum. Moreover, we investigated the accuracy of the TCV measured with both T1 mapping and histology with Bland–Altman analysis and found a similar level of agreement. Noteworthy, our results are in contrast from the ones published from the group of Ide et al., where they showed a difference between ECV and T1 measured in the septum versus the same parameters measured in the total myocardium [In our study, a series of corrections were performed to provide a comparable absolute value expressed in millilitres of TCV for both T1 mapping and histology. In our analysis, TCV measured with T1 was extrapolated from the ECV corrected by LVur group . Finallyocardium . This caocardium . Their rIn this study we were able to show that estimating TCV via T1 mapping could represent a promising technique for the assessment of collagen concentration in comparison to the respective histological measurements. From a clinical standpoint, this might be advantageous because it could avoid the perioperative complications of RV biopsies for a first assessment of myocardial fibrosis and collagen concentration. Moreover, it can be a useful non-invasive way to monitor disease progression and responsiveness to treatment in already chronic patients suffering from cardiomyopathies that would need anyway to undergo CMR control visits. Still, there are some missing points. More studies are needed to assess the sensitivity and specificity of T1 mapping in identifying TCV by comparing it with the histological analysis. Consequently, there is the need to find a physiological reference value of TCV in healthy adults to assess the normality of myocardial collagen concentration. These steps will allow to improve and build new algorithms for a better identification of collagen and fibrosis deposition through CMR.Our study has several limitations. First of all, the animals were healthy, limiting the presence of potential differences within the ventricles concerning the collagen concentration or other inhomogeneities. The formula utilized for the calculation of CVF and developed by Flett et al. has not been validated with the MOLLI sequence. The myocardial density constant utilized has been validated only in humans and may be slightly different in swine. Moreover, the sample size used in our study is small and, thus, our results need to be confirmed with further studies. CMR suffers from a limited spatial resolution, thus partial volume averaging poses a challenge for ECV measures because other components of the ECV (i.e. blood and fat) can bias the evaluation. During imaging, care must be taken to avoid obliquity and ensure the myocardium is perpendicular to the plane of the image. Finally, HR is a known physiologic confounder of ECV mapping through MOLLI , 1.In this study, we showed the potential usefulness of TCV as a non-invasive parameter of collagen concentration for the LV. Further studies are needed to validate this parameter both in healthy and pathological models.


To develop an accelerated motion corrected 3D whole‐heart imaging approach (qBOOST‐T2) for simultaneous high‐resolution bright‐ and black‐blood cardiac MR imaging and quantitative myocardial T2 characterization.Three undersampled interleaved balanced steady‐state free precession cardiac MR volumes were acquired with a variable density Cartesian trajectory and different magnetization preparations: (1) T2‐prepared inversion recovery (T2prep‐IR), (2) T2‐preparation, and (3) no preparation. Image navigators were acquired prior the acquisition to correct for 2D translational respiratory motion. Each 3D volume was reconstructed with a low‐rank patch‐based reconstruction. The T2prep‐IR volume provides bright‐blood anatomy visualization, the black‐blood volume is obtained by means of phase sensitive reconstruction between first and third datasets, and T2 maps are generated by matching the signal evolution to a simulated dictionary. The proposed sequence has been evaluated in simulations, phantom experiments, 11 healthy subjects and compared with 3D bright‐blood cardiac MR and standard 2D breath‐hold balanced steady‐state free precession T2 mapping. The feasibility of the proposed approach was tested on 4 patients with suspected cardiovascular disease.2 = 0.99) was found between the proposed qBOOST‐T2 and T2 spin echo measurements in phantom experiment. Good image quality was observed in vivo with the proposed 4x undersampled qBOOST‐T2. Mean T2 values of 53.1 ± 2.1 ms and 55.8 ± 2.7 ms were measured in vivo for 2D balanced steady‐state free precession T2 mapping and qBOOST‐T2, respectively, with linear correlation of y = 1.02x+1.46 (R2 = 0.61) and T2 bias = 2.7 ms.High linear correlation (y = 1.09 × −0.83, RThe proposed qBOOST‐T2 sequence allows the acquisition of 3D high‐resolution co‐registered bright‐ and black‐blood volumes and T2 maps in a single scan of ~11 min, showing promising results in terms of T2 quantification. To partially overcome this problem, a T2 prepared Bright‐blood and black‐blOOd phase SensiTive (BOOST) IR sequenceThe aim of this work was to develop a novel accelerated and respiratory motion compensated 3D whole‐heart sequence (qBOOST‐T2), which provides co‐registered high‐resolution 3D bright‐blood, black‐blood, and quantitative T2 map volumes from a single free‐breathing scan of ~11 min. This was achieved by extending the BOOST sequence22.1The proposed 3D whole‐heart electrocardiograph triggered qBOOST‐T2 mapping sequence is shown in Figure 2D low‐resolution iNAVs were acquired before the acquisition of each volume to estimate and correct for superior‐inferior (SI) and left‐right (LR) translational respiratory motion, enabling 100% respiratory scan efficiency. A template‐matching algorithm with a mutual information similarity measureEach undersampled translational motion corrected 3D volume was independently reconstructed with a 3D low‐rank patch‐based reconstruction (3D‐PROST).3D affine image registration was performed between the 3 reconstructed volumes. The T2prep‐IR volume provided bright‐blood anatomy visualization, while a PSIR‐like reconstruction2.2EPG simulations were carried out to generate a subject‐specific dictionary. Trigger delay and acquisition window parameters were specified for each simulation according to the heart rate (HR) and mid‐diastolic resting period of the subject. Taking into account the centric k‐space reordering of the acquisition trajectory, the simulated dictionary was generated considering the mean absolute value of the signal for the k‐space central region (40% of the readouts per heartbeat), containing contrast information. Longitudinal magnetization evolution was used to determine the signal magnetization polarity. The dictionary was generated with 3 different T1 values =  ms and variable T2 values in the range (minimum: step size: maximum)  ms.Before matching, 2 PSIR reconstructions were performed between the T2prep‐IR prepared and the nonprepared datasets and between T2‐prepared and nonprepared datasets. These PSIR reconstructions were used to systemically restore signal polarity that would affect the matching with the simulated dictionary. The 3 translational motion corrected volumes were normalized in time by dividing each voxel in each volume by the root mean square of the corresponding voxels in the 3 volumes. The obtained datasets were used to obtain the normalized signal evolution, through the 3 acquired volumes, for each voxel.2.3The proposed qBOOST‐T2 sequence was tested in simulations, in a T2 phantom, on 11 healthy subjects  and on 4 patients with suspected cardiovascular disease . Acquisition was performed on a 1.5T MR scanner  with an 18‐channel chest coil and a 32‐channel spine coil. Written informed consent was obtained from all participants before undergoing the MR scans and the study was approved by the Institutional Review Board.2.3.1EPG simulations were carried out to investigate the matching sensitivity to long T1 and T2 pairs and the T2 dependency on different simulated HRs. Signal evolution for different T1 and T2 pairs, ranging, respectively, between T1 = (800:100:1400) ms and T2 = (40:6:88) ms were simulated and matched to an EPG dictionary generated with T1 =  ms and T2 =  ms. HR dependency was assessed by matching the signal evolution generated with different T2 = (40:6:88) ms, fixed T1 = 1100 ms and variable HR = (40:20:120) beats per min (bpm) to a dictionary with T1 =  ms and T2 =  ms.2.3.2myoc = 52 ms and T2myoc‐diseased = 65 ms). The phantom consists of 6 vials with increasing agar concentrations .3, resolution= 2 × 2 × 4 mm3, TR = 10 s, TEs =  ms and total TA of 2 h and 12 min. The IRSE was acquired with TR = 10 s, TE = 12 ms and TIs =  ms in a total TA = 6 h and 16 min. Reference T2 and T1 values obtained with the SE and IRSE experiments are shown in Supporting Information Table Data acquisition was performed in an in‐house developed T2 phantom to test the sequence ability to differentiate between healthy and diseased myocardium  = 90 degrees, simulated HR = 60 bpm, trigger delay = 700 ms, TE/TR = 1.57/3.6 ms, bandwidth = 822 Hz/pixel, 14 start‐up echoes for iNAVs acquisition, 30 segments per heart beat corresponding to an acquisition window of 110 ms, and acceleration factor of 4 for each volume leading to a total scan time ~3 min. The conventional T2 prepared 2D T2 map was acquired with a bSSFP sequence with FA = 70 degrees, FOV = 290 × 360 mm2, resolution = 1.8 × 1.8 mm2, slice thickness = 8 mm, TE/TR = 1.18/3.5 ms, bandwidth = 1185 Hz/pixel, simulated heartbeat = 60 bpm, trigger delay = 700 ms, T2prep preparations =  ms, 3 recovery heart beats and linear k‐space ordering.Acquisition parameters for qBOOST‐T2 included: bSSFP acquisition with centric k‐space ordering, transversal orientation, resolution = 1 × 1 × 2 mm2.3.33, FOV = 320 × 320 × 96‐104 mm3, TI = 110 ms, T2prep1st‐volume = 50 ms, T2prep2nd‐volume = 30 ms, FA = 90 degrees, TE/TR = 1.57/3.6 ms, bandwidth = 822 Hz/pixel, 14 start‐up echoes for iNAVs acquisition, and acceleration factor of 4 for each volume leading to a total scan time 11 ± 1.2 min. The 3D CMRA dataset was acquired with a fully sampled bSSFP sequence and imaging parameters matching the qBOOST‐T2 acquisition with a single T2prep of 40 ms, resulting in a total scan time 11.5 ± 1.4 min. Imaging parameters for the standard 2D T2 mapping were set as follows: resolution = 1.8 × 1.8 mm2, slice thickness = 8 mm, FOV = 290 × 360 mm2, FA = 70 degrees, TE/TR = 1.18/3.5 ms, bandwidth = 1185 Hz/pixel, T2prep preparations =  ms with 3 heart beats for magnetization recovery, 3 short axis slices  were acquired in a 10 heart‐beats breath‐hold per slice. All acquisitions were electrocardiograph triggered and performed during mid‐diastolic resting period. Trigger delay ranged between 548 and 950 ms and acquisition window ranged between 85 and 125 ms corresponding to 24‐34 segments acquired per heartbeat. The acquisition parameters of the different used sequences are summarized in Supporting Information Table Data were acquired with the proposed qBOOST‐T2, conventional 2D bSSFP T2 mapping, and 3D CMRA sequence with iNAV‐based respiratory motion correction2.3.4The feasibility of the proposed qBOOST‐T2 sequence was tested on 4 patients with suspected cardiovascular disease. Imaging acquisition parameters matched the healthy subject scans. The patients were, respectively, 25, 75, 41, and 63 years old with an average HRs of 45, 72, 85, and 76 bpm. A conventional 2D bSSFP T2 prepared mapping sequence was acquired for comparison purposes with the same imaging parameters used for the healthy subject study.2.42D T2 maps were reconstructed in‐line using the scanner software . Nonrigid motion correction to compensate for in‐plane motion between 2D T2 weighted images and exponential pixel‐wise fitting were performed in‐line on the scanner.qBOOST‐T2 and CMRA raw data were exported from the scanner and reconstructed in MATLAB  on a dedicated workstation . Translational motion correction to end‐expiration was performed individually on each qBOOST‐T2 dataset in vivo. The 3 datasets were independently reconstructed using 3D‐PROST, with reconstruction parameters set as suggested in Bustin et al.The 2D translational motion correction to end‐expiration was performed on the fully sampled CMRA dataset and a sensitivity‐weighted coil combination was performed.2.52.5.1Conventional 2D bSSFP T2 map and 3D qBOOS‐T2 were compared in terms of accuracy with respect to the SE reference. T2 dependency of dictionary T1 was evaluated by matching the measured signal to 3 different dictionaries: T1s 1st dictionary =  ms, T1s 2nd dictionary =  ms, and T1s 3rd dictionary =  ms. HR dependency was assessed by performing different acquisitions with HR = (40:20:120) bpm.2.5.2Quantitative analysis was performed for the 3D T2 maps generated with qBOOST‐T2 and the conventional 2D T2 mapping sequence. 3D T2 maps from qBOOST‐T2 were reformatted to the same slice position as the corresponding 2D T2 maps. Mean T2 values were measured for both sequences by selecting a region of interest (ROI) in the myocardial septum. The standard deviation of the T2 measurements within the ROI was used to quantify the precision of the techniques. Additionally, a Bland Altman analysis was performed to evaluate the agreement between the proposed qBOOST‐T2 mapping technique and the conventional 2D T2 mapping approach.The American Heart Association 17‐segment modelThe percentage errors of variation were averaged across subjects and displayed as bull's eye plots and bar plots. The T2 homogeneity in the whole left ventricle was evaluated for a representative healthy subject by generating a histogram of per‐pixel T2 values and quantifying the T2 distribution through different coronal slices.2.5.3Mean and standard deviation in T2 quantification were evaluated and compared with conventional 2D bSSFP T2 mapping by selecting a ROI in the septum of the myocardium in apical, mid and basal short axis slices. The American Heart Association 17‐segment model was used to compare the conventional 2D T2 maps and the proposed qBOOST‐T2 mapping in terms of mean T2 value and precision across the whole left ventricle for a representative patient.3All data acquisitions and reconstructions were carried out successfully and results are reported hereafter.3.1EPG simulation results are shown in Figure 3.22 = 0.99). A better agreement in T2 quantification was found between qBOOST‐T2 and SE with linear correlation y = 1.09x – 1.67 (R2 = 0.99); however, overestimation of long T2 values was observed.The quantified T2 values obtained with reference SE, 2D bSSFP T2 map, and 3D qBOOST‐T2 are shown in Figure T2 dependency on the T1 dictionary used is shown in Figure The results of the experiments to investigate HR dependency are shown in Figure 3.3Coronal, transversal, short axis, and 4‐chamber views of 2 representative healthy subjects acquired with the proposed qBOOST‐T2 are shown in Figure Short axis reformatted anatomical bright‐ and black‐blood images and T2 map are shown for a different healthy subject in Figure Coronal, 4‐chamber views and coronary reformatted images obtained with bright‐blood qBOOST‐T2 and CMRA are shown in Figure T2 maps generated with the proposed approach were compared with conventional 2D bSSFP T2 mapping qualitatively and in terms of T2 quantification. The 2D short axis views and the reformatted short axis views obtained with qBOOST‐T2 are shown in Figure 2 = 0.61) was found between the conventional 2D bSSFP T2 mapping and qBOOST‐T2. The average T2 values obtained with 2D bSSFP and 3D qBOOST‐T2 sequences were T2 = 53 ± 2 ms and T2 = 55 ± 3 ms, respectively. A statistically significant (P = 0.0003) slight overestimation in T2 quantification was observed with the proposed method. The proposed approach showed a slightly lower precision with respect to the standard 2D T2 mapping technique ; however, it was not statistically significant. T2 quantification obtained with standard 2D bSSFP T2 mapping and qBOOST‐T2 mapping were also compared in a Bland‐Altman analysis  T2prep‐IR preparation module, (2) T2 preparation, and (3) no preparation. The T2prep‐IR prepared dataset provided bright‐blood anatomical visualization, the black‐blood volume was obtained by performing a PSIR reconstruction between the first and third dataset and the 3D T2 map was generated by matching the acquired signal evolution to a dictionary obtained by means of EPG simulations. The use of 2D image‐based navigators allowed SI and LR translational motion correction with 100% respiratory scan efficiency and predictable scan time. Whereas, the use of a 3D patch‐based PROST reconstruction enabled 4× undersampled acquisition preserving good visual image quality.The proposed qBOOST‐T2 has been designed to enable a comprehensive assessment of the heart including anatomical visualization and T2 myocardial tissue quantification in a single free‐breathing scan, thus overcoming some of the limitations of current sequential acquisitions, such as misalignment and long scan times. The 3D acquisition allowed whole‐heart myocardium coverage in comparison to conventional breath‐hold 2D T2 mapping maintaining uniform T2 quantification across the whole left ventricle and across different slices. Additionally, the nearly isotropic high‐resolution nature of the acquisition permitted to reformat the co‐registered bright‐blood, black‐blood volumes, and T2 maps in different orientations  preserving good image quality and uniform T2 quantification in a clinically feasible scan time, in comparison to recently proposed 3D T2 mapping methods with lower resolution that do not allow reformatting the 3D volume in different orientationsThe proposed qBOOST‐T2 approach showed good accuracy and precision with respect to spin echo reference values (high linear correlation) in the phantom experiment. T2 quantification was found to be robust to T1 variability in both simulations and phantom experiments (T2 variability <5%). Sequence simulations showed robustness to different HRs (percentage of variation <5%). Higher dependency on HR was observed in the phantom scan (variability of 10%); however, capability to differentiate between different T2 values ranging between 25 ms and 115 ms was observed.Good delineation of anatomical structures was observed in the bright‐blood volume acquired with qBOOST‐T2 approach. However, lower sharpness was observed in the reformatted coronary qBOOST‐T2 image Figure , which mGood agreement in terms of T2 quantification was observed between T2 maps obtained with the proposed qBOOST‐T2 sequence and standard bSSFP T2 mapping in healthy subjects. A slight T2 overestimation and a lower precision was observed with the proposed approach in comparison to conventional 2D bSSFP T2 mapping. However, the difference in measured precision was not statistically significant. The bias in T2 quantification between qBOOST‐T2 and 2D bSSFP T2 mapping calculated with the Bland‐Altman analysis was 2.7 ms (within the limits of 95%). The slight T2 overestimation of qBOOST‐T2 with respect to 2D bSSFP T2 mapping was likely due to the different k‐space ordering used by both sequences , as has been reported before.A general T2 overestimation across the whole myocardium with respect to conventional 2D bSSFP T2 mapping was also observed in the bull's eye plots. However, T2 quantification was uniform across the whole 3D volume. A lower precision was observed particularly in the inferior part of the heart, which may be explained by the presence of residual motion in the reconstructed images and lower signal to noise ratio due to larger distance to the radiofrequency coils. Additionally, the inferior region of the heart is located close to the edge of the FOV; thus, imperfect shimming could lead to field inhomogeneities that would affect the T2 map. Moreover, a lower signal to noise is expected in the qBOOST‐T2 acquisition due to lower slice thickness.Preliminary results in 4 patients showed a similar trend as noticed in the healthy subject study. A slight T2 overestimation was observed in each acquired short‐axis slice when compared with standard 2D bSSFP T2 mapping, with slightly lower precision. However, the 3D whole heart coverage of the proposed approach provides the flexibility to reformat the acquired volume in any orientation, which could be beneficial for the identification of localized pathologies as shown in van Heeswijk et al.A potential limitation of the proposed work is fat suppression. Different fat suppression techniques are used on each acquired dataset because fat signal evolution differs in each volume. In the first dataset, a STIR approach is used to achieve fat suppression. The inversion pulse of the T2prep‐IR module was used to null the fat signal with an TI of 110 ms. In the second and third dataset, a SPIR approach was used and spectral presaturation FAs of 110 degrees and 130 degrees were used to null fat signal in the second and third volume, respectively. Both TI and SPIR FAs were optimized for a HR of 60 bpm, however, the HR dependency of fat suppression techniques could lead to residual fat signal in 1 or more reconstructed volumes. If a suboptimal fat suppression is achieved in 1 or more of the acquired volumes an unpredictable signal will be matched in the T2 map: depending on the acquired signal evolution, the T2 corresponding to the closest dictionary entry to the measured signal will be matched. Moreover, residual fat signal could generate partial volume artefacts thus affecting the T2 quantification at the myocardium‐fat interface. In the presence of partial volume, the mixed signal will be matched to the closest signal evolution entry in the dictionary; however, it will not reflect the proper T2 value of the voxel. The least square error of the matching process could be used to assess the accuracy of the matching in the presence of partial volume artefacts.The approximation of the standard deviation of the proposed technique used in this study ignores intrinsic variability of underlying T2 because uniform mean T2 values were expected across healthy subjects. However, this approximation is valid only when analyzing normal T2 values and percentages of the mean should be considered in future patient studies.An additional limitation of the proposed technique is the approximation of respiratory motion as pure translational motion in SI and LR directions. Respiration induces additional displacements of the heart such as translational motion in the anterior‐posterior direction, as well as rotation and nonrigid deformation.A further limitation is the sensitivity to arrhythmia. In the presence of arrhythmia, the measured signal would differ from the steady state signal expected in the 3 different interleaved acquisitions, generating a T2 overestimation or underestimation in the matched T2 maps. Prospective or retrospective arrhythmia rejection could be incorporated in the future to overcome this limitation. With a prospective arrhythmia rejection approach, 3 interleaved beats will be rejected in the presence of 1 arrhythmic heart beat and the entire acquisition will be repeated with a stabilized HR; however, this approach will lead to longer and unpredictable acquisition time. On the other hand, by exploiting retrospective arrhythmia rejection, all the datasets will be acquired and the data corrupted by arrhythmic heart beats will be excluded from the reconstruction. However, the reconstructed dataset will be further undersampled (an undersampling factor of 4 is used to accelerate the acquisition); thus, in the presence of high undersampling, the image quality of the reconstructed datasets and, therefore, of the matched T2 maps may be compromised. Validation of the proposed approach in patients with cardiovascular disease and challenging acquisition conditions, i.e., arrhythmic heart beat will be investigated in future studies.5The proposed accelerated qBOOST‐T2 sequence allows the acquisition of 3D co‐registered high‐resolution bright‐ and black‐blood volumes and T2 map for comprehensive assessment of cardiovascular disease in a clinically feasible scan time of ~11 min. The proposed approach shows promising results in terms of accurate T2 quantification when compared with conventional 2D T2 mapping. Future work will include further validation in patients with cardiovascular disease.FIGURE S1 EPG simulations performed to assess the matched T2 dependency on the T1 used to generate the simulated signal. A, Signal evolution of T1/T2 pairs with T2 = (40:6:88) ms and T1 = (800:100:1400) ms were matched to a EPG dictionary with fixed T1 = 1100 ms. High T1 dependency was observed for long T2 values. B, Signal evolution of T1/T2 pairs with T2 = (40:6:88) ms and T1 = (800:100:1400) ms were matched to a EPG dictionary with T1 =  ms. T2 matching percentage error was decreased and a T2 variation < 5% was observed for almost all the simulated signal. C, Maximum variability errors (T1 = 800 and 1400 ms) obtained by matching the simulated signal to a dictionary with fixed T1 (top row) and a dictionary with T1 =  ms (bottom row)FIGURE S2 A, Effect of averaging contiguous slice on T2 quantification and T2 precision. Averaging 6 contiguous slices leads to a reduction of standard deviation in a septal ROI from 5.90 ms to 3.39 ms (percentage of variation of 42.5%), whereas no effect on T2 quantification was observed (T2 variability of only 1.1%). B, T2 intensity profile drawn across a septal region (indicated by the black line) for different number of summed slices. Decreasing resolution in the slice direction leads to an increase of partial volume effects between blood and myocardium. Indeed, a narrower myocardial delineation is observed for a high number of summed slices. Additionally, partial volumes effects are visible in lower resolution images as shown by the black arrowFIGURE S3 A, Three 3D qBOOST‐T2 maps were generated for 1 representative subject with reconstructed resolutions of 1 × 1 × 2 mm3, 1.5 × 1.5 × 3 mm3 and 2 × 2 × 4 mm3 and compared with 2D bSSFP T2 map. B, Mean T2 and T2 precision measured in the septum of the myocardium as function of different reconstructed resolutions for 3D qBOOST‐T2. A reduction in standard deviation is observed, whereas a variability of only 0.96% in myocardial T2 quantification was observed between different resolutions. Table: Mean and standard deviation of T2 measured in the septum for different reconstructed resolutionsFIGURE S4 A, Bull's eye plot of averaged myocardial T2 quantification and precision of the proposed qBOOST‐T2 mapping sequence for patient 2. B, Histogram of per‐pixel T2 distribution through the whole left ventricle. C, Averaged T2 distribution through coronal slices showed a linear correlation of y = −0.03x + 47.3. Uniform T2 quantification is observed in the left ventricleTABLE S1 T1 and T2 values obtained from Inversion Recovery Spin Echo (IRSE) and Spin Echo (SE) experiments on a phantom with 6 vials with different agar concentration . The measured T2 values are within a range than includes T2 of physiological and pathological myocardium (T2myoc = 52 ms T2myoc‐diaseased = 65 ms)TABLE S2 Acquisition parameters used in phantom and in vivo acquisition for 2D bSSFP T2 mapping, 3D qBOOST‐T2 and coronary magnetic resonance angiography (CMRA)TABLE S3 Measured septal myocardial T2 values obtained with qBOOST‐T2 and conventional 2D bSSFP for 4 patients. A general T2 overestimation and lower precision is observed with the proposed techniqueClick here for additional data file.VIDEO S1 Bright‐blood 3D volume acquired with qBOOST‐T2 for a representative healthy subjectClick here for additional data file.VIDEO S2 Co‐registered black‐blood 3D volume acquired with qBOOST‐T2 for same healthy subject shown in Video Click here for additional data file.VIDEO S3 Co‐registered 3D T2 map acquired with qBOOST‐T2 for same healthy subject shown in Videos Click here for additional data file.


The management of mitral valve regurgitation (MR), a common valve disease, represents a challenge in clinical practice, since the indication for either surgical or percutaneous valve replacement or repair are guided by symptoms and by echocardiographic parameters which are not always feasible. In this complex scenario, the use of natriuretic peptide (NP) levels would serve as an additive diagnostic and prognostic tool. These biomarkers contribute to monitoring the progression of the valve disease, even before the development of hemodynamic consequences in a preclinical stage of myocardial damage. They may contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations, thus requiring surgical management rather than a conservative approach. This article provides a comprehensive overview of the available evidence on the role of NPs in the management, risk evaluation, and prognostic assessment of patients with MR both before and after surgical or percutaneous valve repair. Despite largely positive evidence, a series of controversial findings exist on this relevant topic. Recent clinical trials failed to assess the role of NPs following the interventional procedure. Future larger studies are required to enable the introduction of NP levels into the guidelines for the management of MR. Mitral regurgitation (MR) represents one of the most frequent valve diseases with an indication for valve replacement or repair, both as surgical or transcatheter interventional management .The etiology of mitral dysfunction, namely primary or secondary regurgitation, should be clearly identified. In primary or organic MR, the valve apparatus is directly affected as a consequence of a degenerative  or infective  process. In secondary or functional MR, the structure of the components of the valve apparatus, such as leaflets and chordae, is preserved, but an impaired left ventricular (LV) geometry is responsible of an altered balance between closing and tethering forces on the valve. In both abovementioned conditions, MR is responsible for or contributes to the development of LV and left atrial (LA) overload, leading to hemodynamic alterations.According to the most recent European Guidelines , urgent In secondary MR, due to significant operative mortality, high rates of recurrent MR, and the absence of a definite survival benefit, surgery is indicated when concomitant coronary revascularization is required. Even in this circumstance, percutaneous edge-to-edge repair may represent an efficacious option ,5.Although a “watchful waiting” strategy is considered safe and is accepted in asymptomatic patients, the assessment of correct and univocal timing of surgeries still remains a challenge. The identification of symptoms may be difficult due to its subjective nature and to the risk that patients could minimize their clinical manifestations in order to delay surgery, or could progressively reduce their activities as a consequence of an impaired functional capacity. In addition, symptoms may become clear when LV dysfunction is irreversible .In this complex scenario, one of the unmet needs is a more accurate risk stratification, in which biomarkers may represent a useful tool to identify patients with a possibly unfavorable prognosis under conservative management or after mitral valve (MV) surgery.Among several biomarkers available in clinical practice, natriuretic peptides (NPs) have a well-established role in cardiovascular diseases and, particularly, in heart failure (HF) where they reflect cardiac overload, LV systolic and diastolic dysfunctions, and are associated to cardiovascular outcomes .N-terminal portions (NT-proANP and NT-proBNP) are released in response to increased myocardial stretch, as a consequence of volume or pressure overload. NPs exert several cardiovascular and renal actions mediated by the type A natriuretic peptide receptor through the second messenger cGMP. The effects of NPs are able to counterbalance hemodynamic congestion through the regulation of electrolytes, water balance, and permeability of systemic vasculature. Moreover, they inhibit the renin–angiotensin–aldosterone system and the sympathetic nervous system. At the cellular level, a modulatory role on cellular growth and proliferation is recognized [Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and their inactive cognized ,9,10. Socognized ,12. Morecognized ,14.The aim of our review is to analyze the current available evidence on the role of NPs in the management, risk evaluation, and prognostic assessment of patients with MR before and after surgical or percutaneous valve repair.Several studies have investigated the association between increased levels of NPs in patients with MR, parameters of LV dysfunction, and cardiovascular outcomes.An analysis of data obtained in 1399 patients from 15 studies found a positive relationship between levels of NPs and LV end-systolic parameters, such as the LV end-systolic index (LVESI) and LVESD . Mayer aIn a prospective study conducted in 124 patients with chronic primary MR, Detaint and colleagues analyzed the relationship between BNP level, MR degree, LV and LA remodeling, and prognosis . BNP levIn another study, BNP level >105 pg/mL had stronger predictive power compared to the most common parameters of MR severity, such as an effective orifice regurgitant area (EROA) and LVESD . In 49 pThe prognostic role of BNP level in the management of MR has also been examined during exercise.Exercise BNP level was strongly correlated with those measured at rest . PatientAccording to the abovementioned results, BNP level may be used in clinical practice as a complementary tool for echocardiographic exams and exercise tests in order to identify those patients who are more likely to experience death from cardiovascular causes, and HF and cardiac hospitalizations, thus requiring surgical management, rather than a conservative approach. In addition, NPs may represent an essential tool to monitor the progression of the valve disease before the development of hemodynamic consequences in a preclinical stage of myocardial damage.However, some controversial aspects deserve to be better-clarified. First of all, as documented by the abovementioned studies, it is still difficult to establish a univocal cut-off level able to identify MR patients at elevated cardiovascular risk, since different levels of NPs have been identified in the different studies. To overcome this problem, Clavel et al. introduced the BNP ratio, which is derived from a measured BNP value divided by the expected value related to the age and sex of each patient .This parameter behaves as a significant independent prognostic marker of outcomes in valve heart disease patients, including MR patients under medical treatment ,29. HoweOther critical issues relate to the appropriate time interval that should be considered for the subsequent measurements of the NP level, and the magnitude of changes of NP values between baseline and subsequent assessments, which may be related to a poor clinical outcome. In addition, age, AF, renal function, and body weight are known modulators of NP levels, thus representing potential confounders . FinallyDuring the last few years, percutaneous edge-to-edge MV repair with the MitraClip  device has acquired increasing importance as a treatment option, especially in patients with HF with an elevated surgical risk. However, many patients are still being treated with the surgical MV repair or replacement, which represents the gold-standard procedure. Apart from the reduction of MR, both percutaneous and surgical interventions may produce several hemodynamic benefits, reducing LV and LA pressure and volume overload and, as a consequence, the myocardial wall stretch ,3.In this context, several studies have assessed the role of NPs in the management of patients treated with MV repair or replacement, investigating the sensibility of these biomarkers in identifying subjects with a worse response to the performed interventional procedure and with a lower chance of survival.In a study involving 65 patients treated with edge-to-edge valve repair, a low NT-proBNP level, measured 6 months after the procedure, was associated with a significant reduction in LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) and to an improvement in LV and LA longitudinal strain . Worse rAfter percutaneous valve repair, improvements in 6-minute walking distances and a decrease in LV volumes were paralleled by a significant reduction of NT-proBNP level .Hwang and colleagues identified a BNP cut-off level of 125 pg/mL associated with a higher risk of cardiac death and re-hospitalization for cardiac causes in 117 patients who underwent surgical MV replacement . InteresAs for the pre-operative level, controversial findings were frequently reported with regard to the post-operative level. In 59 patients who underwent percutaneous MV repair, achieving a reduction of MR, an improvement of functional class, and structural reverse cardiac remodeling (reduced LA volume and LVESD and increased LVEF), the NT-proBNP level did not decrease significantly . SimilarFinally, as for the pre-surgical management, it has not been clearly established which biomarker should be chosen, which cut-off value should be considered for the risk assessment of the patients, and which interval for serial monitoring of NPs has the best accuracy.Two recent trials have become available in patients subjected to MV repair. The MITRA-FR  for Severe Functional/Secondary Mitral Regurgitation) trial, conducted in patients with severe secondary MR, showed that percutaneous MV repair added to standard pharmacological therapy was unable to reduce the rate of death or unplanned hospitalizations for HF at 1 year compared to those who received medical therapy alone .The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) study demonstrated that the transcatheter MV repair reduced the rate of hospitalizations for HF and all-cause mortality within 12 and 24 months of follow-up . Althoug2 in MITRA-FR vs. 101 ± 34 mL/m2 in COAPT) [2 vs. 31 ± 10 mm2, respectively) [Several possible mechanisms have been proposed to explain the discrepant findings, mostly focusing on the different echocardiographic characteristics of the subjects included in the two trials ,47. The n COAPT) ,45,46,47ctively) ,45,46,47ctively) . In suchIn this complex scenario, the differences in the baseline NP levels between the two studies may mirror the different pathophysiological mechanisms. In the COAPT trial, both NT-proBNP and BNP levels were significantly higher than in MITRA-FR , and it may be argued that they were more related to MR severity than to either LVEF or LV diameter ,45. In fThe most plausible pathophysiological explanation for the better association of NPs with pre- and post-procedural outcomes may be their optimal capacity to reflect cardiac performance in different hemodynamic conditions. Of note, lack of a sufficient number of studies using ANP as a marker in the management of MR does not currently allow to make a robust comparison with BNP.Several efforts have been made over the last few years to investigate the role of other biomarkers in the MR condition, and have been previously reviewed . More reThe neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, both markers of functional and structural kidney damage, were shown to predict mortality in high-risk patients undergoing percutaneous MV repair . HoweverOf note, some evidence of the role of other parameters in the outcome prediction of MR patients has been collected. For instance, it was found that abnormalities of the calcium-phosphate metabolism may influence the health-related quality of life in patients with severe MR . AmeliorFinally, one study reported the negative prognostic impact of pre-procedural anemia in patients who underwent PMVR with a higher baseline NT-proBNP level .Based on the evidence collected so far, markers of mechanisms involved in the cardiac remodeling process may be considered as complementary prognostic tools to the NP level.The management of MR still represents a real challenge for physicians, since the assessment of symptoms is difficult and the recommended diagnostic exams, such as the echocardiogram, are often not accurately performed. It is well-known that NP secretion occurs in the presence of atrial and ventricular stretch, as a consequence of pressure and volume overload, and that NPs are independent predictors of mortality and morbidity in patients with severe MR. Due to their feasible measurement and to their significant association with echocardiographic parameters of LV dysfunction and of impaired filling, these biomarkers may represent an important tool to identify patients at elevated risk of adverse clinical outcomes, in which early surgical or percutaneous intervention should be considered .Moreover, the NP level has also been documented to be a powerful independent predictor of reduced cardiac event-free survival in patients treated with surgical or transcatheter valve repair or replacement, thus representing potential instruments to significantly improve the evaluation of a short- and long-term prognosis after these procedures.Although some controversies still exist, the majority of findings discussed in our review article are encouraging, and indicate NPs as potentially useful biomarkers for the clinical management of MR. Further larger studies are needed to solve key issues, that is, to better define which biomarker should preferably be used among NPs, which rest and eventually stress cut-off levels could clearly identify high-risk patients, and which degree of variation between serial measurements may have the best clinical accuracy. It is hoped that these future studies will allow the introduction of NP levels into the guidelines for the management of MR.


Aim of the present study was to describe the left ventricular longitudinal strain (LS) in all myocardial layers in patients with severe aortic stenosis (AS), preserved left ventricular ejection fraction (LVEF) in different LV geometry and to compare LS analysis before and early after acute LV unloading provided by transcatheter aortic valve implantation (TAVI). 68 patients were enrolled. LS was measured from the endocardial layer (Endo-LS), epicardial layer (Epi-LS) and full thickness of myocardium  before and after TAVI. Patients were divided in two groups accordingly with relative wall thickness (RWT): concentric LV hypertrophy (cLVH) vs eccentric LV hypertrophy (eLVH). Less impaired values of LS at baseline were observed, in all layers, in patients with cLVHas compared to patients with eLVH . A significant improvement in endocardial LS (Endo-LS) after TAVI was detected only in cLVH. Our findings documented that concentric LVH had better basal strain function and showed a better myocardial recovery after TAVI compared to eLVH. Concentric LVH (cLVH) was characterized by a RWT ≥ 0.42, while eccentric LVH (eLVH) by a RWT < 0.42. These myocardial changes are progressive and associated with symptoms’ onset and prognosis worsening. More severe LVH and, specifically, eLVH pattern seems to be associated with poor prognosis after aortic valve replacement (AVR) [In patients with aortic stenosis (AS), left ventricular hypertrophy (LVH) is considered to be an adaptive response to the increased afterload , 2. LVH nt (AVR) . Howevernt (AVR) . More rent (AVR) . Multilant (AVR) . Transcant (AVR) . HoweverAim of the present study was to examine the acute effect of TAVI in terms of pressure unloading, on LV mechanics using multilayer LS by 2D speckle-tracking echocardiography (ST-E) in different patterns of LV geometry to better understand the subset of AS patients that have potentially more benefits from LV unloading.2/m2 by echocardiography, accordingly with current guidelines [We enrolled 68 patients  with severe symptomatic AS and preserved LVEF, scheduled for TAVI. Inclusion criteria were: (a) severe AS defined by an aortic valve area ≤ 0.6 cmAll patients underwent 2D and 3D echocardiography at baseline and 5 ± 2 days after TAVI. LS by ST-E was measured from the endocardial layer (Endo-LS), epicardial layer (Epi-LS) and full thickness of myocardium  before and after the procedure. ST-E analysis was performed with QLab software v.13 by Philips. Analysis included the collection of clinical characteristics and 2D/3D echocardiographic features, such as LV volumes indexed for body surface area (BSA), and ejection fraction (LVEF), LV mass, LV diastolic function, right ventricular (RV) dimension and function and RV-LS. Patients with significant aortic regurgitation or mitral valve disease, pace-maker (PMK) rhythm and/or left bundle branch block (LBBB), unstable coronary artery disease (CAD) were excluded to avoid confounders. Patients with poor acoustic window and uncontrolled heart rate were excluded as contraindications to perform ST analysis. All patients fulfilled LVH hypertrophy criteria by LV mass index. Patients were divided in two groups, accordingly to RWT measurement. cLVH was more represented than eLVH in our study population . All clinical and demographic characteristics were collected, including stable CAD. The Ethic committee of “Policlinico Umberto I Hospital- Sapienza, University of Rome” approved the present study, and all patients provided written informed consent. Comprehensive echocardiographic evaluation is showed in Fig. TAVI was performed using a standard trans-femoral or -subclavian technique. Both balloon-expandable and self-expandable valves were used for this purpose. Patients with stable CAD and significant stenosis (> 70%) underwent revascularization with percutaneous angioplasty and drug-eluting stent implantation at least one month before the procedure. A self-expandable valve was implanted in 40 patients (60%), while a balloon-expandable valve was implanted in 28 patients (40%).Statistical analysis was performed using SPSS software v.23. Continuous variables were reported as mean ± standard deviation, and were compared using Student’s t test or the Mann-Whitney rank sum test for unpaired and paired comparisons, as appropriate. Categorical variables were reported as percentages of individuals. The χ2 test or Fisher’s exact test were used to compare qualitative variables. Differences were considered statistically significant when p < 0.05.2 vs. 62 ± 14, p = 0.066) and higher values of LS at baseline in all layers . Valvulo-arterial impedance (Zva) was similar in the two groups. After TAVI, a significant improvement in Endo-LS was observed only in cLVH group . No significant improvements were recorded in eLVH patients after TAVI. Standard echocardiographic parameters didn’t show any significant amelioration immediately after TAVI. No differences in type of valve implanted were found in the two groups.No significant differences in baseline clinical characteristics were found between the two groups, including the presence of stable CAD, as showed in Table The present study showed (a) the presence of less impaired LS values at baseline, in all layers, in patients with cLVH than in patients with eLVH; (b) a significant improvement of Endo-LS early after TAVI, only in cLVH.LVH in AS occurs as a response to pressure overload and cLVH pattern is more frequently observed than eLVH, particularly when valve regurgitation and LV systolic dysfunction are excluded .The presAccordingly, LS is known to be impaired in AS. It was previously demonstrated that the mechanisms involved in the alteration of LS in AS are (a) the development of LVH and (b) LV fibrosis, which is related with both increased afterload and concomitant CAD . Layer-sPrevious studies already explored LS behavior in different myocardial layers after TAVI , 16. ShiThe main limitation of the present study is the small sample size that could mask other differences between groups. Follow-up data are not provided, since the study is not powered for MACCE. Finally, there is no control group for comparison.Our results demonstrated that patients with severe aortic stenosis and cLVH geometry had a better improvement after TAVI, described by multilayer LS analysis, compared to eLVH. This result highlights the possible role of LV geometry to improve the selection of the stage of valve disease, identifying who could have less benefit from the reduced afterload after aortic replacement.