A series of technical refinements over the past 30 years, in combination with advances in perioperative management, have resulted in dramatic improvements in the survival of patients with univentricular heart. While the goal of single-ventricle palliation remains unchanged – normalization of the pressure and volume loads on the systemic ventricle, the strategies to achieve that goal have become more diverse. Optimal palliation relies on a thorough understanding of the changing physiology over the first years of life and the risks and consequences of each palliative strategy. This review describes how to optimize surgical decision-making in univentricular patients based on a current understanding of anatomy, physiology, and surgical palliation. Over the past 30 years, there has been a dramatic improvement in the survival of patients with univentricular heart , 2. The The ultimate goal of staged univentricular palliation is to normalize the volume and pressure work of the functional ventricle while pumping blood fully saturated with oxygen, regardless of the underlying cardiac anatomy . HoweverEarly perinatal management of patients with univentricular heart is focused on identification of the anatomy (which may constitute an immediate risk to the patient after birth) and on stabilization with the usual measures to control the volume and pressure load to the ventricle while enabling adequate systemic delivery of oxygen. These goals must be achieved regardless of the underlying anatomic substrate . Attention should be paid to the delicate and dynamic balance between the systemic and PVR ratio, leading to ongoing re-evaluation and adjustments in management as the PVR falls .Evaluation of the neonate with single ventricle is directed at identifying answers to the following questions: (1) is there a reliable source of systemic blood flow? (2) is there a reliable source of pulmonary blood flow? (3) Is there any impediment to pulmonary venous return? and (4) Is there an appropriate balance between the systemic and pulmonary circulations? . Non-invpulmonary circulation  and those with ductal-dependent systemic circulation . In either case, maintenance of ductal patency is critical to providing adequate systemic oxygen delivery.In cases when there is a significant impediment to pulmonary or systemic circulations, the ductus arteriosus can be used to provide a reliable source of pulmonary or systemic blood flow. Patients in whom a patent ductus arteriosus is necessary may be divided into those with ductal-dependent Since, initially described by Olley and colleagues in 1976 and later by the Green Lane Unit , 9, prosIn cases where the pulmonary and systemic circulations are connected in parallel, blood leaving the functional ventricle may enter either the pulmonary artery or the systemic circulation. The underlying anatomy, and in particular, the presence of either pulmonary or systemic outflow obstruction will have an important influence on the relative balance between pulmonary and systemic blood flow Table . In the 2 and pO2; but the manipulation of respiratory gas exchange is often sufficient to provide balanced pulmonary blood flow in the early post-natal period  present important challenges. The presence of atrioventricular valve regurgitation results in an additional volume load on the already loaded ventricle. This commonly leads to congestive heart failure and not infrequently a gradual and progressive onset of ventricular dysfunction. Early control of pulmonary blood flow to reduce additional volume loading is essential. Not infrequently – particularly among patients with a single right ventricle or those with a common atrioventricular valve – control of pulmonary blood flow can be associated with a significant reduction of the valve regurgitation , 16. In The presence of ventricular dysfunction can be associated with late diagnosis or intrinsic myocardial dysfunction. Commonly, the dysfunctional ventricle is unable to meet the work requirements of the single-ventricle circulation, leading to circulatory failure and end organ dysfunction. As stated previously, early attention to reducing the volume and pressure load on the ventricle is critical. If obstruction to systemic blood flow is present, an unobstructed pathway must be secured with the use of PGE1 or with an intervention. While manipulation of respiratory gas exchange in combination with inotropic support may be sufficient, some patients will require early surgical control of pulmonary blood flow. Depending on the underlying anatomy, this may be performed using either a main pulmonary artery band or, if patency of the ductus arteriosus is necessary, branch pulmonary artery banding (see below). In all patients, this will reduce the Qp/Qs, volume load, ventricular work, and usually will lower the end-diastolic pressure over time. Moreover, in those with ductal-dependent circulations (such as HLHS), it may have the added benefit of augmenting systemic diastolic pressure and enhancing coronary perfusion.In contradistinction, obstructed pulmonary venous return is often a serious and frequently insurmountable problem. The timing of intervention varies, from emergent in the case of intact atrial septum to semi-elective in the case of moderate obstruction or less. Alternatively, if the anomalous pulmonary venous drainage is unobstructed, control of pulmonary blood flow may reduce the pulmonary venous gradient. Repair can then be deferred to a later date – ideally the second-stage procedure .Although an atrial septectomy or repair of total anomalous pulmonary venous connections may resolve an anatomic obstruction , fetal dFinally, the management of single-ventricle patients with non-cardiac congenital anomalies or with postnatal illness (particularly sepsis) remains difficult. In this scenario, caution should be utilized when choosing conventional treatment measures. While systemic vasoconstrictors may be essential for maintaining blood pressure in septic patients, in univentricular heart patients, they can lead to disproportionate increases in SVR resulting in the rapid development of pulmonary overcirculation, volume overload, and poor oxygen delivery. In hypotensive patients, clinical and ecocardiographic evaluation should assist in identifying the underlying mechanism: vasodilatation, poor cardiac function, or maldistribution of cardiac output. In the case of sepsis, epinephrine provides the most effective support. The use of dopamine in single-ventricle patients is controversial; as it has been shown to increase the systemic oxygen demand offsetting any improvement in systemic oxygen delivery . Pure vaThe goals of initial palliation are to provide unobstructed systemic blood flow, well-balanced pulmonary and systemic circulations with controlled pulmonary blood flow, and unobstructed pulmonary and systemic venous return . Although the long-term goals include normalization of the ventricular volume load and provision of normal systemic oxygen delivery, the elevated PVR characteristic of the newborn period requires a staged approach to achieve these long-term goals. As part of the initial surgical palliation, relief of any systemic outflow tract and pulmonary venous obstructions must also be undertaken. Thus, the precise procedure to accomplish the goals will depend on the underlying anatomy but may include the creation of a reliable and controlled source of pulmonary blood flood through a systemic–pulmonary shunt, limitation of pulmonary blood flow via main pulmonary banding, repair of aortic coarctation and aortic arch hypoplasia, or a combination of these (including the Norwood procedure). Relief of any pulmonary venous obstruction by either reconstruction of stenotic anomalous pulmonary venous connections or a complete atrial septectomy should be performed as needed.2Sat <70%) is present  is determined by the severity of the baseline flow imbalance. In patients with reduced pulmonary blood flow and low Qp, the degree of cyanosis is the best indication for when to proceed with surgical palliation. Creation of a reliable and effective source of pulmonary blood flow with a shunt procedure (see below) should be undertaken when severe cyanosis  suggest the need for pulmonary banding. Signs will usually worsen as the PVR falls postnatally. Occasionally, there is a reasonable balance between systemic and pulmonary circulation, while the pulmonary vascular bed is protected from high pressure and high flow. In some cases, these patients can exhibit growth and development in the first months of life, while the pulmonary vascular bed matures and develops. In this scenario, patients may then proceed directly to a superior cavopulmonary connection at an appropriate age.In patients with excessive Qp and signs of heart failure, control of pulmonary blood flow is essential to permit somatic growth and eliminate the volume load to the ventricle while the normal post-natal decrease in PVR takes place , 25. MosIt should be noted, that in patients with single-ventricle and discordant ventriculo arterial connection, pulmonary artery banding can lead to significant systemic outflow obstruction. In these patients, systemic outflow is dependent on flow through the ventricular septal defect (bulboventricular foramen) and the hypoplastic outflow chamber. In this scenario, pulmonary artery banding is usually associated with significant myocardial hypertrophy, leading to outflow obstruction in as many as 70–100% of patients , 27. MorAmong patients with inadequate pulmonary blood flow , augmentation of pulmonary blood flow through the use of a systemic-to-pulmonary shunt may be necessary. Multiple techniques are of primarily historical importance, including the classic Glenn, the classic Blalock–Taussig, the Waterston, and the Potts shunts. In current practice, nearly all shunts are a modified Blalock–Taussig shunt (mBTS) consisting of a PTFE graft connecting the proximal innominate artery and the right pulmonary artery.In most cases, the shunt is performed via a median sternotomy with the variable use of cardiopulmonary bypass. This incision has several advantages over the traditional lateral thoracotomy, including the ability to ventilate both lungs, more central placement on the pulmonary arteries (minimizing the risk of lobar branch compromise), access for ligation of the arterial duct, and the ease of cannulation for cardiopulmonary bypass where required . In addiThe diameter of the PTFE shunt is the primary determinant of its resistance. Alterations in the length of the tube or in its position on the arterial tree play a smaller, but still important role. In neonates weighing 3.5 kg, a 3.5-mm shunt is usually appropriate. In slightly larger infants or those with smaller pulmonary arteries, placing the shunt more proximally within the systemic circulation may provide additional flow without the dramatic decrease in resistance apparent with a step-up to a 4-mm shunt. However, shunts originating in locations other than the innominate artery may have a higher early mortality risk, although confounding with morphologic variation preventing the use of the innominate artery may play an important role . Despitepost hoc analysis of that population suggested a benefit with the use of aspirin in this population, with a 40% relative risk reduction in the incidence of the primary outcomes   is a common practice but based primarily on observational data. A retrospective observational study by Li and colleagues suggests a beneficial impact of aspirin in preventing shunt thrombosis and improving survival in shunted patients . More reombosis) . Based oombosis) . A randoPreservation of antegrade pulmonary flow may lead to pulmonary overcirculation and volume overloading. This can be particularly deleterious among patients with atrioventricular valve regurgitation, in whom maintaining pulmonary arterial patency is associated with worsening regurgitation and higher risk of early mortality . Not infAlthough rare in univentricular patients, the presence of a dynamic component to pulmonary flow limitation increases the complexity of early postnatal management. In the patient with a single functional ventricle, hyper cyanotic spells may result in a rapid deterioration of ventricular function, myocardial ischemia, and death. However, preservation of the native pulmonary blood flow at the time of insertion of a systemic-to-pulmonary artery shunt in order to provide adequate Qp during episodes of dynamic obstruction may lead to a extremely challenging management of excessive Qp at baseline. In these cases, it seems preferable to ligate and divide the main pulmonary artery, relying instead on a single and fixed source of pulmonary blood flow.Provision of a reliable and unobstructed systemic outflow pathway represents one of the main tenets in the management of single-ventricle patients. Failure to relieve systemic outflow obstruction during initial palliation has several deleterious consequences. If the outflow obstruction is distal to the source of pulmonary blood flow , the result will be increased pulmonary blood flow and lower systemic output. This leads to pulmonary overcirculation, inadequate protection of the pulmonary vascular bed associated with the elevation of PVR, and ultimately increased volume load on the single ventricle. Most importantly, the outflow obstruction results in an important pressure load on the ventricle with consequent hypertrophy, increased myocardial stiffness, and elevation in end-diastolic pressure. At the time of conversion to a cavopulmonary connection (and the loss of the systemic blood pressure as a driving force for pulmonary blood flow), elevations in end-diastolic pressure increased PVR and may preclude Fontan completion or result in early Fontan failure and poor survival , 45–47.The most common procedures used in the relief of systemic outflow tract obstruction are the DKS and Norwood procedures. In both cases, the main pulmonary artery is used as the main pathway for the systemic outflow. In cases when the systemic outflow obstruction is associated with aortic arch hypoplasia and/or coarctation of the aorta, then Norwood procedure is the procedure of choice .As noted above, the threshold for performing either a DKS or a Norwood procedure in patients with a univentricular heart and potential or mild systemic outflow obstruction is a matter of controversy. If creation of a DKS is considered, placement of a pulmonary band should be tempered by the distortion of the pulmonary (neo-aortic) root and valve, which can be associated with neo-aortic insufficiency at the time of DKS. The negative feedback loop initiated by the presence of ventricular outflow obstruction stimulates myocardial hypertrophy leading to worsening outflow obstruction and the potential for long-term myocardial alterations as the result of early pressure loading of the ventricle. Given these considerations, the threshold for performance of a procedure to relieve outflow obstruction should be low with the goal to provide a durable and reliable solution that would avoid the need for repeated reinterventions. Evidence-based guidelines would require a prospective trial.The Norwood procedure is commonly performed among patients with univentricular hearts and systemic outflow obstruction. In spite of nearly three decades of experience, little consensus exists regarding the most appropriate source of pulmonary blood flow, techniques of intraoperative management, and cerebral protection, and whether hybrid or conventional procedures provide the most appropriate palliation.Since initially described, the source of pulmonary blood flow has evolved over time, including a direct RV to PA conduit, central shunt, and modified BT shunt –50. The In order to answer these questions, a multi-center randomized trial was undertaken to compare the two shunt types . AlthougOur current practice is to prefer the RV–PA conduit in patients with aortic atresia where the risk of coronary ischemia is particularly high in the absence of antegrade aortic blood flow. Otherwise patients receive an mBTS due to our concerns regarding the need for additional interventions and long-term impact on ventricular function. Importantly, ongoing modifications of the RV–PA conduit, including the use of ring reinforced grafts and dunking of the graft into the ventricle , may decThe combination of stenting of the ductus arteriosus and banding of the branch pulmonary arteries as initial palliation for hypoplastic left heart syndrome was initially described by Gibbs et al. in 1993 . It was However, with additional follow up, it has become apparent that the hybrid procedures can mitigate only some of the risk associated with these factors. Consistent with broad results in surgery among patients with low birth weight , it doesFinally, it is clear that patients undergoing hybrid palliation are affected by the obligatory distortion of the central pulmonary arteries and pulmonary arterial growth, resulting in an increased rate of pulmonary arterial interventions Figure  59, 61,,61, 66. Given the potential morbidity of the hybrid procedure and the inability to demonstrate a significant improvement in outcomes, its usefulness remains a matter of controversy. The use of branch PABs for the temporary control of pulmonary blood flow seems particularly advantageous in the setting of initial hemodynamic instability refractory to usual medical management, reversible risk factors, or need for an immediate non-cardiac surgical intervention  , 75, 76.The superior cavopulmonary connection  has a significant salutary effect on cardiac function. The second-stage procedure relieves the volume load on the single ventricle while maintaining systemic oxygen delivery . This reIn light of these physiologic advantages, and aiming to reduce the inter-stage mortality among patients with a systemic-to-pulmonary artery shunt, the timing of the SCPC has been shifted toward an earlier age than the usual 5–6 years –83. The Alternatively, patients who have a reliable and controlled source of pulmonary blood flow have the innate advantage of having a pulmonary vascular bed that is protected from high pressure and flow, while affording appropriate oxygen saturations. In this case, the option of a primary SCPC should be considered after 10–12 weeks of age .The type of superior cavopulmonary connection is of little importance, as it does not appear to influence long-term outcomes . While tControversy continues to exist regarding the management of additional pulmonary blood flow at the time of SCPC. Additional pulmonary blood flow may be provided by either leaving a previous systemic–pulmonary shunt intact at the time of SCPC, or by leaving antegrade flow through a banded or stenotic native pulmonary artery , 89. TheHowever, there is no convincing evidence to support these benefits. Because of both the increase in venovenous collaterals and somatic growth, the higher oxygen saturations may not persist through Fontan palliation , 98, 99.Furthermore, preservation of additional pulmonary blood flow has the potential for significant side effects, predominantly related to the persistent volume load on the single ventricle . This isIt does not appear that either strategy increases the likelihood of Fontan candidacy , 94, 99.Care should be exercised in situations where the native pulmonary outflow tract is ligated. In these cases, the native pulmonary artery stump has the potential to act as a nidus for thrombus formation –109. VarInitially, the Fontan procedure was described for the treatment of tricuspid atresia and was intended to use atrial contractions as a “pulmonary ventricle” –112. HowNevertheless, in many situations, a TCPC provides the best long-term palliation for patients with a complex cardiac defect not amenable to biventricular repair. Alternatively, it has been suggested that an SCPC  could be the final palliative stage in patients with unsuitable hemodynamics for Fontan completion or as a means to avoid the long-term ill effects of chronic passive congestion , 105. AlIn 1977, Choussat and colleagues published the criteria for an ideal Fontan candidate Table  116). S. S116). Both ventricular dysfunction and atrioventricular valve regurgitation also result in a higher risk of Fontan failure , 118. InThe Fontan procedure has been considerably modified since the description of a direct atriopulmonary connection in a patient with tricuspid atresia by Fontan . A varieApproximately, 2/3 of all TCPC procedures performed in the United States are extracardiac conduits and the remainder are predominantly lateral tunnels . The proAmong the advantages of the lateral tunnel are the potential for pathway growth enabling early Fontan completion, often between 12 and 30 months of age , as wellAlternatively, the extracardiac conduit TCPC must be performed at an older age due to the lack of growth potential in the conduit. Some perceived advantages to the procedure include: no need for myocardial ischemia or even cardiopulmonary bypass , and smaOverall, the variability in diagnosis, operative technique, and perioperative management as well as limited long-term follow-up continues to plague studies attempting to identify a significant advantage of one technique or another. Whether hybrid approaches to Fontan completion  will ultimately result in better early and late outcomes remains unclear , 141.In the current era, the majority of Fontan procedures are performed with “fenestration” , 129. ThMost centers performing lateral-tunnel Fontans routinely perform fenestrations , 158, soClosing of fenestrations has not resulted in improvement in exercise capacity , and theThe long-term complications of circulatory physiology lacking a pulmonary pump are manifested. As noted above, transition to the TCPC from atriopulmonary connections has ameliorated some of the complications associated with Fontan’s original technique, but has not eliminated them , 128. EvDue to limitation in donor availability, cardiac transplantation cannot provide a comprehensive treatment option for those patients with single-ventricle physiology, but has become the bail-out strategy for selected patients with a failed palliative strategy either with or without preserved ventricular function. Nevertheless, it should be understood that this does not constitute a cure but rather a more manageable form of palliation, which may be associated with a better quality of life . In the Alternatively, transplantation can improve outcomes by eliminating the risk factors, which commonly lead to high mortality among patients with palliated univentricular circulation. For example, severe atrioventricular valve regurgitation or ventricular dysfunction significantly increases the risk of single-ventricle palliation , but unlEven the “perfect” Fontan has a recognized attrition rate over time . The exaDespite the binary nature of the surgical decision regarding univentricular palliation, “univentricular” lesions represent a spectrum of anatomic subtypes, which – at the milder end – may be amenable to a two-ventricle repair. The definition of “milder end” and the determination of whether a borderline anatomy is adequate to pursue a biventricular circulation remain challenging. Different level of obstruction in these borderline cases makes the evaluation difficult and the surgical intervention to address them a challenge. While obstruction at the aortic level and even at the level of the systemic outflow can be effectively solved, it is often the inflow in the ventricular cavity  that presents the greatest challenge to determine the feasibility of a two-ventricle repair. However, the decision about which patients may benefit from a two-ventricle repair remains highly dependent on the specific lesion and the institutional expertise to accomplish these complex repairs with acceptable morbidity and mortality.Patients with left heart anomalies represent a wide spectrum of anatomy and physiology. The decision-making is fairly clear at ends of the spectrum, but becomes more difficult when patients fall in the so-called borderline category. Despite extensive studies –208, thez-score <−5) are clear indications for single-ventricle palliation. While some centers have had success with staged left ventricular recruitment in patients with left-sided structures with z-scores as low as −5, this is a technically challenging process requiring multiple procedures and the long-term results compared to single-ventricle palliation are uncertain , a tripartite right ventricle, and a patent pulmonary valve can undergo an initial biventricular repair with excellent results although a systemic–pulmonary shunt is not infrequently needed to provide adequate pulmonary blood flow in the neonatal period  are significantly worse when the tricuspid valve r repair –220. How pathway . When it pathway . Patientl period .A particularly challenging group is the one comprised by patients with PA/IVS and right ventricular dependent coronary circulation, in whom single-ventricle palliation carries a very high risk, not only initially but during subsequent palliation , 223. ThSurgical decision-making regarding the pursuit of a biventricular circulation in patients with unbalanced atrioventricular septal defects is particularly difficult and depends on the adequacy of the AV valve inflow. Detailed analysis of echocardiographic variables aimed to identify which patients would have a successful biventricular repair has been facilitated by the creation of the modified atrioventricular valve index  . While aWhile case series may provide evidence of what can be done by a specific surgical team, they do not necessarily provide data to support a particular pathway at all centers. In this context, multi-institutional studies, such as those from the CHSS , 226, maDespite the advances in the operative and perioperative management of patients with univentricular heart, morbidity and mortality remain high. Decisions made in the early post-natal period may have important consequences for both early survival and long-term morbidity. In particular, the surgical strategy chosen – whether univentricular palliation or biventricular repair, hybrid versus traditional procedures, choices regarding the most appropriate pulmonary blood flow – will affect management throughout a patient’s life. Unfortunately, there is lack of conclusive data to guide these choices. Further studies are required in many areas to identify determinants of the optimal surgical strategy in individual patients. In the absence of definitive data, surgical decisions must rest on subjective assessment grounded in a thorough understanding of the anatomy, physiology, and potential consequences of each strategy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated.Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase eNOS Glu298Asp SNP retrospectively.140 non-dialysis CKD patients, who had cardiac magnetic resonance (CMR) imaging and tissue doppler echocardiography as part of two clinical trials, were genotyped for The median estimated glomerular filtration rate (eGFR) was 50mls/min and left ventricular ejection fraction (LVEF) was 74% with no overt diastolic dysfunction in this cohort. There were significant differences in LVEF across eNOS genotypes with GG genotype being associated with a worse LVEF compared to other genotypes . After multivariate analysis,  GG genotype was associated with a worse LVEF, and increased LV end-diastolic and systolic index .eNOS Glu298Asp rs1799983 polymorphism in CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses. Chronic kidney disease (CKD) is a major public health issue, mainly due to accelerated cardiovascular disease, affecting an estimated 10–16% of the population in developed countries. Non-traeNOS) and heart failure [In the general population, there has been interest in the association between the Glu298Asp polymorphism within endothelial nitric oxide synthase  SNP rs1799983 genotyping was performed using Taqman technology as previously described [Whole blood (8.5ml) was collected in PAXgene Blood DNA Tubes  which were then frozen and stored at -80°C. Samples were defrosted at room temperature for 2 hours before starting the DNA extraction process. DNA extraction was undertaken using the PAXgene Blood DNA Kit  as previously described . All DNAescribed . 384-welCMR was performed on a 1.5-T scanner . Serial contiguous short axis cines were piloted from the vertical long axis and horizontal long axis of the right and left ventricle  in accordance with previously validated methodologies . AnalysiTransthoracic echocardiography  was performed by an experienced echocardiographer. All parameters were measured in triplicate according to American Society of Echocardiography recommendations  and analPulse wave velocity, augmentation index and ascending aortic distensibility were common measures of arterial stiffness and distensibility in the two randomised control trials, they have been included here. Pulse wave analysis was performed on the radial artery using a high-fidelity micromanometer . The peripheral arterial waveform was used to generate a central arterial waveform using a validated transfer function . The same system was used to determine aortic pulse wave velocity by sequentially recording ECG-gated carotid and femoral waveforms as previously described . CMR dateNOS genotype. Secondary outcomes included: LV end-diastolic volume indexed to body surface area (LVEDVI), LV end-systolic volume indexed to body surface area (LVESVI) and S’ lat . As there is much debate over which parameters of diastolic function should be measured as well as their variability in assessment [eNOS genotype. The “diastolic” parameters included: e’ lat , E/e’ lat , mitral valve E/A , LVMI (left ventricular mass index), mitral valve propagation velocity (MV VP) and LAVI .The primary aim was to evaluate the association between LV ejection fraction (LVEF) with sessment , six diaBaseline demographics and cardiac investigations were compared across the genotype groups, using Kruskal-Wallis (continuous data) and Fisher’s Exact tests  as appropriate. The relationship between these was then investigated using regression analysis. Initially, univariate linear regression models were produced, with variables being log-transformed where there was evidence of a non-linearity. Multivariate regression models were used  in order to adjust for potentially confounding factors.A cluster analysis was then performed, to divide patients into groups based on the values of a range of diastolic parameters. The Two-Step cluster analysis in IBM SPSS 19 was used, with the number of clusters determined automatically . Demographic factors were then compared between the resulting clusters, using t-tests or Fisher’s Exact test, as applicable. All analyses were performed using IBM SPSS 19 , with p<0.05 deemed to be indicative of statistical significance.eNOS SNP rs1799983 patient genotype frequency was GG in 47% (62/132), TG in 39% (51/132), and TT in 14% (19/132). This distribution was within Hardy-Weinberg equilibrium bounds (p>0.05). Patient demographics are presented in 2, with 85% of patients prescribed an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker. The most common renal disease group was glomerular disease, with 16% of the cohort patients been diagnosed with IgA nephropathy on renal histology.Genomic DNA was successfully genotyped in 132 (>94%) patients. The ’ lat was seen, but this failed to reach statistical significance (p = 0.106). As shown in Univariate analysis revealed a significant difference across genotypes for LVEF and LVESVI  limits the generalizability of its findings, the exclusion criteria does allow removal of these potential external factors that affect both eNOS activity and left ventricular function, allowing a more ‘pure’ analysis of eNOS polymorphism association with LVEF in early CKD. Long-term follow-up of the present study population is also desirable to monitor how these patients’ LVEFs and heart failure symptoms develop as their CKD progresses, in relation to their eNOS genotype.The influence of genotype on cardiac function and outcome may be context-specific. Of note, McNamara et al suggested a beneficial effect of GG genotype outcome in patients with established, clinically evident heart failure . Whilst This study benefits from a uniform technique of detailed CMR assessment of cardiac volumes and systolic function, and very careful clinical phenotyping. Although no association with “diastolic dysfunction” parameters derived from echocardiography and genotype was evident, the size of the cohort means that such an effect cannot be excluded, and further study in larger cohorts is required.eNOS Glu298Asp polymorphism in non-dialysis CKD patients is associated with relevant sub-clinical cardiac remodelling as detected by CMR. This gene variant may therefore represent an important genetic biomarker, and possibly highlight pathways for intervention, in these patients who are at particular risk of worsening cardiac disease as their renal dysfunction progresses.In summary, S1 Table(DOCX)Click here for additional data file.


This study examines the role of T1- and T2-mapping versus today's T1- and T2-weighted imaging standard along with interpretation modes for discrimination of AMI from CMI.T2-weighted imaging, late enhancement (LGE) as well as T2-mapping (3 single-shot SSFP-images), native T1-mapping , and T1-mapping 10min after 0.2mmol gadobutrol using non-product sequences. Image analysis included: 1) Visual assessment: Five independent readers assessed the presence (yes/no) of an infarct-like myocardial lesion. 2) Quantitative assessment per segment: Myocardial T2- and T1-relaxation times were determined for every segment and correlated to LGE. 3) Quantitative assessment per pixel: Based on reference T2- and T1- relaxation times, abnormal pixels were identified and correlated to LGE.Eight male patients with acute ST-elevation myocardial infarction underwent CMR at 3T (Siemens Verio) acutely and after >3 months. Imaging techniques included: T2-weighted images showed an infarct-like lesion in 82.9% of AMI and 27.8% of CMI, LGE in 95.0% / 100%, T2-map in 69.2% / 35.0%, native T1-map in 86.8% / 57.5%, and post-contrast T1-map in 95.0% / 91.9%. 2) The pattern of segmental abnormalities of T2- and T1-relaxation times in infarcted segments compared to remote myocardium was not consistent for a confident diagnosis of AMI and CMI. 3) Pixelwise threshold-based analysis of T2- and T1-maps exposed infarcted regions in the myocardium in AMI and CMI. The presence of T2-abnormalities in the chronic state and the classification of remote pixels as abnormal limited its diagnostic value. The figure shows the various images and maps as well as segmental relaxation times of one representative patient.1) T2- and T1-maps based on predefined thresholds that separate normal from abnormal was the most promising approach to read maps, whereas visual assessment and segmental analysis of T2- and T1-maps were less favorable. The discrimination of AMI and CMI is not facilitated using the tested T2- and T1-maps.Referring to the studied mapping sequences, pixelwise analysis of TThis project was supported by the Else Kröner-Fresenius Stiftung  (2010_A70).


Diffuse myocardial fibrosis (MF) in dilated cardiomyopathy (DCM) is closely related to systolic and diastolic cardiac failure and could be identified as a major independent value prediciting clinical outcome. It results from elevated levels of collagen and is therefore associated with an expansion of the extracellular volume (ECV). Up to now, the detection of MF requires myocardial biopsy. Recent reports indicate that CMR T1-Mapping has the potential to detect MF non-invasively. We compared the ECV values derived from T1-mapping with the collagen volume fraction (CVF) as meausured in histological samples.All CMR examinations were performed in a 1.5 T CMR scanner . Short axis slices covering the left ventricle were acquired using SSFP-sequences to measure volumes and ejection fraction. T1- relaxation times were measured from 24 patients  with DCM before and 15 minutes after injection of gadolinium-DTPA contrast agent . T1-maps were created out of 11 mid-ventricular short axis views with increasing inversion times  using a single breath-hold modified Look-Locker inversion-recovery sequence  in late diastole. The formula for calculating the extracellular volume fractions is given in Figure The DCM patients had a mean left ventricular ejection fraction (LVEF) of 39 ± 16%. Average ECV fraction was 27 ± 4% and CVF was 19 ± 4% in our study population. There was a strong correlation between ECV and CVF (r = 0.85; p = 0.01, Figure CMR-based ECV assessment may offer the potential to serve as a non-invasive tool for the quantification of MF in DCM and possibly in other cardiomyopathies as well. Further studies are needed to investigate its impact on clinical outcome prediction in DCM patients.None.


Both delayed and premature liberation from mechanical ventilation (MV) are associated with increased morbimortality. Positive pressure ventilation exerts beneficial effects in individuals with cardiogenic pulmonary edema; inspiratory fall in intra-thoracic pressure during spontaneous breathing trial (SBT), in its turn, may precipitate cardiac dysfunction through abrupt increase in venous return and in left ventricular afterload.Determine the impact of radiological signs of pulmonary congestion prior to submission to SBT on weaning outcomes in a mixed ICU population.A prospective, observational study in an adult medical-surgical ICU. All enrolled patients met eligibility criteria for weaning from MV. Traqueostomized subjects were excluded. The primary end point was SBT failure, defined as inability to tolerate a T-piece trial during 30 to 120 minutes, in which case patient was not extubated. An attending radiologist applied a radiological score (RS)There was a total of 170 SBTs procedures; SBT failure eventuated in 28 (16.4%). Nineteen patients (11.2%) had systolic heart failure (ejection fraction < 35%), 4 (2.4%) had chronic obstructive pulmonary disease (COPD) and 31 (18.2%) had been intubated due to respiratory sepsis. One hundred thirty-three patients (78.3%) were extubated at first attempt. RS was similar between SBT failure and success subjects , which means only intersticial lung congestion for both groups. Receiver operating characteristic (ROC) curves analysis demonstrated fail accuracy (area under curve [AUC] = 0.58) of CXRs prior to T-piece trial for discrimination between SBT failure and success individuals. There was no correlation between fluid balance in the 48 hours preceding SBT and RS (ρ = -0.13).Radiological findings of pulmonary congestion should not delay SBT indication since they did not predict greater probability of SBT failure in medical-surgical critically ill population.


Ventricular fibrosis in adult congenital heart disease (ACHD) has been shown to relate to adverse clinical markers., 2 NovelTen adult repaired Tetralogy of Fallot patients aged ≥16 years with glomerular filtration rate>30ml/min completed clinical CMR scans acquired by a single operator on a 1.5T Siemens Avanto for volumetric and functional biventricular assessment. LGE imaging was performed 10 minutes after 0.1mmol/kg intravenous gadobutrol administration .o (BH) and 50o (FB), pixel bandwidth 140Hz (BH) 977Hz (FB) with acquisition window 166ms (BH) 196ms (FB) were set. Inversion times were adjusted for myocardial nulling throughout, and kept constant between both sequences when acquiring identical slice locations in long and short-axis views. When inversion time drift was minimal, transverse navigator-gated 3D LGE imaging was performed as per published protocol as a reference standard.4Interspersed breath-hold (BH) segmented gradient echo and free-breathing (FB) motion-corrected balanced steady state free precession phase-sensitive inversion recovery (PSIR) pulse sequences were acquired with identical typical imaging parameters of: field of view 380x320mm, matrix 256x144, 6mm slice thickness with 4mm gap for short-axis stacks, and acceleration factor (GRAPPA) 2. Repetition time/echo time of 8.3/3.8ms (BH) 2.7/1.7ms (FB), flip angle 255 image confidence scores and semi-quantitative RV LGE scoring.1Blood-myocardium and Gd-myocardium contrast-to-noise ratios (CNRs) were also compared.Anonymised, blinded image analysis was carried out by two experienced observers assessing RV LGE image quality,RV LGE was present in all patients and LV LGE in 7 patients . There was reasonable interobserver agreement when scoring the extent of RV LGE (α=0.605) with good overall agreement in quantifying the extent of RVOT and VSD patch scar Figures  and 2. IFree-breathing LGE provides comparable, diagnostic image quality to conventional 2D BH LGE imaging and may be practical for clinical use, especially for patients unable to breath-hold or with arrhythmias that would otherwise compromise image quality.British Heart Foundation, NIHR Cardiovascular Biomedical Research Unit of Royal Brompton & Harefield NHS Foundation Trust and Imperial College London.


Myocarditis is the most common finding in patients presenting with chest pain, ECG changes, raised troponin and culprit-free coronary angiograms. Adverse events, such as arrhythmias, heart failure and death can occur in the absence of significant left ventricular (LV) impairment and myocarditis should not be considered benign when systolic function is normal at presentation. We currently do not know how to predict which patients will deteriorate. In addition, poorly understood risks of sudden death and cardiovascular events persist in this group.We sought to assess changes in cardiovascular magnetic resonance (CMR) feature tracking (FT) parameters between baseline and follow up scan in myocarditis patients with LV ejection fraction (EF) above 55% on admission to see if FT may help predict interval changes in ejection fraction and possibly adverse outcomes.We prospectively followed 33 consecutive patients presenting with chest pain, troponin elevation and unobstructed coronaries. 17 of these had LVEF above 55% and were included in the current analysis. Baseline scans were performed during admission and follow-up within 3 months. Three dimensional peak LV strain, strain-rate and myocardial velocities were measured (TomTec feature tracking software) for both baseline and follow up scans using 2 chamber (2c), 4 chamber (4c) and 3 short axis slices; basal (sAb), mid (sAm) and apical (sAa) using cine SSFP images. Paired t-test was performed to compare interval parameters.Mean age was 35.8 years and 12 were male. There was no significant difference in the mean EF between baseline and follow up (61.26% ± 4.5% (±1SD) vs 61.82% ± 4.5%, p=0.304). 2 patients at follow developed mild LV systolic dysfunction . Baseline 4c peak longitudinal velocity (figure FT is a sensitive technique to document change in cardiac function when ejection fraction is normal or unchanged. In addition, FT parameters have the potential to predict change in cardiac function. Further studies assessing FT in myocarditis are required to assess potential for improving outcome prediction in myocarditis.MK has received research funding from Barts Charity.


Evaluation of sensitive myocardial mechanics with speckle tracking echocardiography (STE) across the lifespan may reveal early indicators of cardiovascular disease (CVD) risk. Epicardial adipose tissue (EAT) and left ventricular (LV) myocardial dyssynchrony; subclinical risk-factors of CVD, are of particular clinical interest. However, the evolution of EAT and LV-dyssynchrony across the lifespan, and their influence on myocardial dysfunction remains unclear. We aimed to establish a profile of the healthy aging-heart using conventional, tissue-Doppler imaging (TDI) and speckle-tracking echocardiography (STE), while also exploring underlying contributions from EAT and LV-dyssynchrony towards LV myocardial mechanics, independent of blood biology.Healthy males aged 19–94 years were recruited through University-wide advertisements in Victoria and New-South Wales, Australia. Following strict exclusion criteria, basic clinical and comprehensive echocardiographic profiles  were established. LV-dyssynchrony was calculated from the maximum-delay of time-to-peak velocity/strain in the four LV-annulus sites (TDI), and six LV-segments . Epicardial fat diameter was obtained from two-dimensional grey-scale images in the parasternal long-axis. Blood biological measures included glycemia, hsCRP, triglycerides, total cholesterol, high-density and low-density lipoprotein levels.Three groups of 15 were assigned to young (<40 years), middle (40–65 years), and older (>65) aged categories. Five participants were excluded from STE analyses due to inadequate image quality. Decreased longitudinal strain, increased circumferential apical strain and LV twist were age-related. Moreover, independent of blood biology, significant increases were observed across age categories for EAT , longitudinal STE-dyssynchrony , and circumferential-basal STE-dyssynchrony . These variables collectively explained 37% and 31% (p < 0.01) of longitudinal strain and LV twist, respectively.This study enabled comprehensive profiling of LV mechanics at different stages of aging using sensitive echocardiographic technology. Novel findings included increased epicardial fat, and both longitudinal and circumferential LV-dyssynchrony across the healthy age groups. These factors may be key underlying contributors to myocardial dysfunction during aging, and their recognition may promote an advanced understanding of early signs of cardiovascular disease. Specifically, epicardial adipose tissue (EAT), measured feasibly by echocardiography, is strongly associated with myocardial lipid content; a potentially major contributor to LV dysfunction in populations with metabolic disorders ,15. HoweFurthermore, non-uniform contraction of LV myocardial walls due to declining electromechanical synchronicity (LV-dyssynchrony) may result in myocardial inefficiency , and couThe primary aim of this cross-sectional study was therefore to establish a comprehensive profile of LV mechanics across different age categories of healthy males, using conventional, TDI and STE echocardiography. A secondary aim was to explore how EAT and LV-dyssynchrony change with age, and quantify their underlying contribution to important measures of LV myocardial mechanics, independently of blood-biology, within this population.Participants provided informed consent prior to commencement of testing, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the Human Research Ethics Committee (HREC) of the Australian Catholic University, Melbourne, Australia. Volunteers were recruited through advertisements, and all participants provided informed consent. Inclusion criteria were males aged over 18 years with no maximum age limit, no prior cardiovascular disease history, diabetes mellitus, dyslipidemia, or hypertension, no routine medication, and (to avoid highly trained athletes) practising less than 10 hours per week of moderate to intense physical activity. Volunteers were screened with verbal interviews and written questionnaires. We recruited males from three age categories: younger than 40 years (Y); 40 to 65 years (M); and older than 65 years (O).Stature, body mass, and body mass index (BMI) were recorded. Blood pressure was measured with a digital sphygmomanometer  after 15 minutes lying in the supine position. Physical activity was quantified using the International Physical Activity Questionnaire modified for elderly populations .Fasted serum concentrations of glucose, triglycerides, total cholesterol, high-density lipoprotein (HDL), low-density lipoproteins (LDL), and high-sensitivity C-reactive protein (hsCRP) were analysed at a clinical pathology laboratory .m), early diastolic (Em), and late diastolic (Am) velocities were assessed at the mitral annulus of the LV, in apical four  and two (anterior and inferior) chamber views. The E/Em ratio, recorded from the mitral annulus lateral wall, was used as an index of LV filling pressure. The tricuspid annular plane systolic excursion (TAPSE) and TDI Sm velocity were also assessed on the lateral (free) wall of the right ventricle. EAT diameter was manually measured on the free wall of the right ventricle from the two-dimensional grey-scale image in the parasternal long-axis view, as previously described [Participants underwent transthoracic echocardiogram and electrocardiogram examination by the same experienced operator, following standard recommendations . Images escribed .The STE mode of two-dimensional strain imaging was used to measure more sensitive myocardial mechanics. Offline analyses were performed in the circumferential axis at the base, papillary-muscle level, and apex of the LV , as well as in the longitudinal axis , using software described above. In the respective B-mode two-dimensional grey-scale cine-loops, a region of interest was manually placed along the endocardial border, and automatically covered myocardial thickness to the epicardial border. Six segments were subsequently analysed in each view. Cine-loops without adequate endocardial border definition, frame rate (>60 Hz), and image tracking were excluded from analyses. The cine-loops were animated, and LV longitudinal strain, strain rate (SR), and time to peak strain/SR were obtained in the apical four-chamber view. Circumferential strain, SR, time to peak strain/SR, and rotation were obtained from the short-axis view at the LV base and apex. LV twist was calculated as the instantaneous difference between apical and basal rotation. To adjust all STE variables for inter-participant differences in heart rate, the time sequence was normalized to the percentage of systolic duration  using a toolbox generated in our laboratory (Scilab 4.1) . Inter am (systolic dyssynchrony) or peak Em (diastolic dyssynchrony) at the annulus of the septal and lateral walls , and inferior and anterior walls . For STE LV-dyssynchrony, time taken from the start of QRS to peak strain in the six LV segments was measured in both longitudinal  and circumferential  axes. LV-dyssynchrony was evaluated using the maximum delay technique in the four (TDI) or six (STE) segments. This modality of measuring LV-dyssynchrony is more sensitive than the Yu index or opposing wall delay [TDI LV-dyssynchrony was measured by recording time taken from the start of QRS complex to peak Sll delay . Clinicall delay  and 100 ll delay  for TDI r correlation analyses were performed between age, cardiac variables, and blood biology. Univariate analysis of co-variance (ANCOVA) was performed to test the strength of the relationships between LV-dyssynchrony and age; after the effects of glucose, total cholesterol and hsCRP were controlled. A stepwise linear regression model assessed the predictive role of LV-dyssynchrony on major indices of myocardial mechanics . Analyses were performed using SPSS Version 16.0 for windows (SPSS Inc), with statistical significance set at p < 0.05.It was predicted that a minimum of 13 participants in each population sub-group  would allow detection of a significant difference if the mean of the major cardiac variables was between 1 and 1.25 standard deviations higher than the mean value between the groups  . After vParticipant recruitment is described in Figure Mean ages of participants were 25.7 ± 6.1 (Y), 49.3 ± 8.8 (M) and 77.7 ± 9.8 (O). Participant age ranged from 19 to 94 years. Age groups did not differ in body mass, BMI, systolic and diastolic blood pressure, hsCRP, triglycerides, HDL, LDL, total cholesterol, and glucose. Stature was lower in O than M and Y groups (p < 0.05) . However, diastolic function was impaired across the age groups. E/A ratio was lower in O than both M and Y (p < 0.001), without differences between M and Y. Em was lower in both O and M than Y (p < 0.001), without differences between O and M. Deceleration time of E and LV filling pressure (E/Em) were greater in O than Y (p < 0.05), but not different from M. Isovolumic relaxation time was more prolonged in both O and M than Y (p < 0.05), but O and M were similar.Among results from RV analyses (Table m was lower in both O and M than Y (p < 0.05), without differences between O and M. EAT diameter was greater in O than both M and Y (p < 0.001), while M was also greater than Y (p < 0.001).Results from the es Table  showed nlongitudinal strain and diastolic SR . However, apical circumferential strain was similar in O and M. Apical circumferential diastolic SR was unaltered by age . TDI-derived maximum delay did not differ between O and M, nor M and Y. In contrast, STE-derived longitudinal maximum delay was greater in O than both M and Y (p < 0.001), while also greater in M than Y (p < 0.05). Additionally, STE-derived circumferential maximum delay at the base was greater in O than both M and Y (p < 0.05), while also greater in M than Y (p < 0.05). No inter-group differences existed for STE-derived circumferential maximum delay at the apex.Measures of LV-dyssynchrony across the age groups are presented in Figure r = 0.79), TDI Em (r = 0.78), circumferential-basal STE LV-dyssynchrony (r = 0.77), E/A ratio (r = 0.75), EAT (r = 0.73), LV twist (r = 0.68), and longitudinal strain (r = 0.62) . Age was also significantly related to hsCRP (r = 0.40) and triglycerides (r = 0.35) (both p < 0.05). Furthermore, some cardiac variables also correlated strongly with blood biology, including; apical circumferential rotation and TDI Am with total cholesterol , apical circumferential systolic SR with hsCRP (r = 0.42), TDI Em with fasting glucose (r = 0.42), and EAT with triglycerides (r = 0.42) and hsCRP (r = 0.40) . After controlling for total cholesterol, fasting glucose, and hsCRP; age remained correlated to longitudinal STE LV-dyssynchrony .Age was significantly associated with the following cardiac variables: longitudinal STE LV-dyssynchrony  while circumferential STE LV-dyssynchrony at the base was associated with LV twist (r = 0.52 p < 0.05). Circumferential STE LV-dyssynchrony at the apex was not associated with any indices of myocardial mechanics. EAT was also associated with longitudinal STE LV-dyssynchrony (r = 0.65), TDI Em (r = 0.60), longitudinal strain (r = 0.50), circumferential STE LV-dyssynchrony at the base (r = 0.44), and LV twist (r = 0.44) . A stepwise linear regression model revealed that the combination of EAT, longitudinal STE LV-dyssynchrony, and circumferential STE LV-dyssynchrony at the base explained 37% of the variability in longitudinal strain, and 31% of the variability in LV twist .Longitudinal LV-dyssynchrony was associated with longitudinal strain .Previous studies of LV myocardial function and dyssynchrony in aging people have not observed individuals older than 89 years of age ,17,18,28m ratio (a measure of LV filling pressure) was elevated in O participants, both systolic and diastolic arterial blood pressures were similar across the age-groups. Analysis of cardiac function at the more regional  level was therefore justified.The present study found mild LV hypertrophy and more impaired diastolic function in the O group than M and Y groups, supporting other longitudinal studies showing LV remodeling and diastolic dysfunction across the lifespan, despite preserved LV ejection fraction -6,30. ThWe revealed decreasing TDI-derived diastolic myocardial velocity across the age-groups, agreeing with other aging studies -35. We aThe first major novel finding from the current study was the increased EAT across the age-groups. Echocardiography-derived EAT is consistently and strongly associated with myocardial lipid content ,43. PrevElevated levels of fibrosis and lipid content in the more mature myocardium may also slow signal conduction , consequLV-dyssynchrony and EAT may be underlying factors responsible for altered myocardial mechanics in older healthy males. Only two MRI studies have observed increasing myocardial dyssynchrony in healthy aging people ,18, whilThe potential effect of age on dyssynchrony may permit clinicians to accept a certain ‘normal’ level of LV-dyssynchrony in healthy older people. In the present study, half of the healthy older participants reached clinical threshold values for both longitudinal and circumferential STE dyssynchrony ,26, despThe cross-sectional design has limitations. While the number of participants in our study may appear limited, our sample size was carefully estimated and reached significance between groups. The discarding of some poor quality cine-loops, inherent to echocardiography, was a limitation; with a standard percentage of rejection , despiteWe established a broad cardiac profile in healthy males of three different age-categories: demonstrating a likely age-associated decline in diastolic function and longitudinal deformation, with a compensatory increase in apical circumferential deformation, rotation and LV twist. For the first time with echocardiography, we showed increasing EAT, longitudinal, and circumferential-basal LV-dyssynchrony across three incremental age-groups of healthy males, independent of the effects of blood biology. We found these variables together significantly explained the variability in longitudinal deformation and LV twist (two major markers of LV mechanics), possibly through pro-inflammatory and pro-fibrotic pathways in the myocardium. Understanding the healthy aging-heart and its typical evolution may assist in the early distinction and prevention of cardiovascular diseases in healthy aging people.The authors declare that they have no competing interests.TM, GN, and EC recruited participants. EC conducted all echocardiographic and clinical measurements. GN, FD and EC conducted statistical analyses. FD and EC drafted the paper, and GN and PO reviewed, corrected and helped finalise the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/14/95/prepub


Heart failure with preserved ejection fraction (HFpEF) constitutes a clinical syndrome in which the diagnostic criteria of heart failure are not accompanied by gross disturbances of systolic function, as assessed by ejection fraction. In turn, under most circumstances, diastolic function is impaired. Although it now represents over 50 % of all patients with heart failure, the mechanisms of HFpEF remain understood, precluding effective therapy. Understanding the pathophysiology of HFpEF has been restricted by both limited access to human myocardial biopsies and by the lack of animal models that fully mimic human pathology. Animal models are valuable research tools to clarify subcellular and molecular mechanisms under conditions where the comorbidities and other confounding factors can be precisely controlled. Although most of the heart failure animal models currently available represent heart failure with reduced ejection fraction, several HFpEF animal models have been proposed. However, few of these fulfil all the features present in human disease. In this review we will provide an overview of the currently available models to study HFpEF from rodents to large animals as well as present advantages and disadvantages of these models. Heart failure is amongst the leading causes of death and disability worldwide and can be defined as the end result of any abnormality in cardiac structure and function that leads to impaired ventricular filling or ejection .Heart failure can be divided into two distinct entities, i.e. heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). HFrEF is related to systolic dysfunction and characterised by the inability of the myocardium to contract and eject enough blood. In turn, HFpEF is associated with diastolic dysfunction while systolic function is normal or near-normal (hence preserved ejection fraction) . MoreoveMyocardial remodelling in HFpEF is characterised by abnormal diastolic left ventricular (LV) function resulting from conditions such as increased stiffness, abnormal ventricular-arterial interaction, increased vascular stiffness, endothelial dysfunction, chronotropic incompetence, impaired relaxation and/or cardiovascular reserve function. Among these, the most important mechanisms underlying diastolic dysfunction are disturbed myocardial relaxation and/or altered passive properties of the ventricular wall. Its phenotype is frequently, but not necessarily always, associated with increased interstitial fibrosis with LV concentric remodelling/hypertrophy and atrial enlargement  rat was selectively bred from Sprague-Dawley presenting the highest values of blood pressure. Dahl/SS is characterised by hypersensitivity to sodium intake and represents the most published HFpEF animal model . When feThe deoxycorticosterone acetate (DOCA) salt-induced rat model represents a pharmacologically induced model of hypertension. DOCA is administered by intraperitoneal or subcutaneous injection at 7 weeks of age, 1 week after a unilateral nephrectomy. This combination results in hypertension, renal hypertrophy, nephrosclerosis, cardiac hypertrophy and perivascular fibrosis within 4–5 weeks of chronic DOCA treatment . The DOCChronic stimulation with pro-hypertrophic agents, such as angiotensin II and isoprenaline, has been used as a model of systolic and diastolic dysfunction as well as LV hypertrophy. Angiotensin II-treated rodents show evidence of hypertension, increased LV hypertrophy, fibrosis and expression of natriuretic peptides, which result in diastolic dysfunction confirmed by increase/worsening in LV isovolumetric relaxation time (IVRT), myocardial performance index, τ, LVEDP, E/E’ along with decreased E/A, without changes in LV dimensions, mass, or ejection fraction . In the Transverse-aortic constriction is a well-established surgical technique for inducing LV chronic pressure overload and hypertrophy in rodents. Moderate transverse-aortic constriction imposed at an early age triggers concentric LV hypertrophy with compensated chamber performance, markedly with prominent diastolic filling abnormalities. Transmitral flow profile showed a ‘restrictive’ filling pattern with increased early (E-wave) and decreased late (A-wave) diastolic transmitral filling velocities, augmented E/E’ and left atrial diameter, more rapid deceleration of the early filling wave as well as a shortened IVRT. These abnormalities became progressively more exaggerated at 12 and 18 weeks [A major limitation of using aortic-banded or hypertensive models is that the majority of patients with HFpEF continue to have heart failure symptoms even when the blood pressure is controlled. Conversely, less than 50 % of HFpEF patients have LV hypertrophy and often show no evidence of LV dilatation, thus making the value of the current preclinical model questionable .Approximately one-third of HFpEF patients have type 2 DM and cardiovascular disease is the leading cause of morbidity and mortality in diabetic patients. Interestingly, diastolic dysfunction represents an early cardiac manifestation of the deleterious effects of DM, since young diabetic individuals predominantly display diastolic abnormalities, whereas HFrEF rarely develops before middle age in obese diabetic individuals . Insulinob/ob mice and the leptin receptor-deficient db/db mice, whose altered leptin homeostasis leads to obesity due to hyperphagia, hyperglycaemia, hyperinsulinaemia, insulin resistance and diabetic complications at different time points [Many models of type 2 DM recapitulate the features of HFpEF patients, including leptin-deficient e points .Db/db mice develop cardiac hypertrophy as evidenced by increased LV mass and wall thickness at 9 weeks of age, which is associated with a smaller LV end-diastolic volume. The progression of diabetic cardiomyopathy is accompanied by increased production of reactive oxygen species and interstitial fibrosis [min, and prolonged relaxation. At this age, transthoracic echocardiography confirmed preserved systolic function with elevated IVRT and reduced E/A, clearly indicating diastolic dysfunction [db/db mice induced the expression of markers of hypertrophy and fibrosis but did not impact greatly on cardiac structure or lead to HFpEF [fibrosis . Five-mofunction . The admto HFpEF .Ob/ob mouse is an obesity and diabetic animal model that shows evidence of diastolic dysfunction possibly due to cardiac lipid accumulation [Ob/ob mice develop myocardial hypertrophy and triglyceride accumulation, which parallels LV diastolic dysfunction as confirmed by decreased E/A [mulation . Ob/ob mased E/A . Progresased E/A .fa and cp). These models are usually associated with other risk factors, including hypertension and/or diabetes, with some of them developing diastolic dysfunction or HFpEF.The increase in global incidence of obesity predicts a continuous rise of the burden of cardiovascular diseases. This is particularly true for HFpEF, as obesity has a prevalence of 41–46 %, is associated with an increased risk of hypertension, dyslipidaemia and diabetes and thus represents an independent risk factor for its development . Many avZucker rats were originally bred to be a genetic model of obesity and hypertension. The obese Zucker rat demonstrates a consistent increase in LV mass and early diastolic dysfunction with prolonged IVRT . In contThe Otsuka Long-Evans Tokushima Fatty (OLETF) rat was derived by selecting spontaneously diabetic rats displaying polyuria, polydipsia and obesity from an outbred colony of Long-Evans rats . The OLEDahl/SS/obese rats, derived from Dahl/SS and Zucker crossing, have been recently established as a new model of metabolic syndrome. At 15 weeks of age, female Dahl/SS/obese rats present with LV diastolic dysfunction, marked LV hypertrophy and fibrosis, associated with increased cardiac oxidative stress and inflammation .fa) with lean spontaneously hypertensive heart failure prone male rats , sharing a common genetic background with Wistar Kyoto rats [2max, showing, for the first time in an animal model, an important corresponding feature of HFpEF human diagnosis - exercise intolerance. In parallel, there is LV hypertrophy and left atrial dilation  mouse offers a good model of cardiac dysfunction associated with ageing. At 6 months of age, this animal model displayed a significant reduction of E/A ratio, E’ and E’/A’ along with increased EDPVR, fibrosis and TGF-β expression when compared to the control group (SAMR1). No differences in systolic function or mean arterial pressure were reported in SAMP8 mice .FVB/N mice represent a robust inbred strain and males display diastolic dysfunction at 12 months, with an E/A < 1 while, in females, this phenotype is not observed . In contAlthough the large number of rodent models has importantly contributed to our understanding of the underlying causes and mechanisms of LV diastolic dysfunction, rodents have inherent limitations due to their size, cardiac structure and function compared to larger mammalian species, in particular the human heart. Therefore, experimental models of human heart failure have also been recapitulated in large animal models, which have been particularly useful in elucidating several important pathophysiological aspects of diastolic dysfunction and HFpEF , through the Cardiovascular R&D Unit (FCT nº. 51/94) and the Academy of Finland, Finnish Diabetes Research Foundation, and Finnish Foundation for Cardiovascular Research.


Cardiac magnetic resonance (CMR) increasingly adds to clinical conformation of the diagnosis in patients with suspected myocarditis. The proposed Lake Louise Consensus Criteria ("any-two" approach) can separate from chronic forms of myocardial inflammation. However, both global enhancement ratio (GRE) and T2-weighted imaging are underutilized, due to poor reproducibility and high susceptibility to artefacts. T1 and T2 mapping by CMR projects tissue-dependent relaxation times. T2 mapping has been recently proposed as a robust and accurate technique to identify areas of focal myocardial oedema. Our aim was to investigate the value of quantitative T2 values in discrimination between health and disease, and separation between active/acute myocarditis and chronic convalescent stage of the disease.Twenty-four patients with acute presentation of viral myocarditis and twenty-three subjects in clinical convalescence were recruited. Thirty-three healthy subjects were served as controls. All subjects underwent CMR study for routine assessment of myocardial oedema, function and scar by at 3-Tesla scanner. T2 values were acquired in midventricular short-axis slice (mSAX) using GraSE sequence. We examined regional T2 values in patients and controls. T2 values are presented as an average of the six segments per mSAX. Secondly we investigated the differences between visually involved and remote myocardium Patients with acute myocarditis and chronic myocarditis showed significantly raised T2 values [controls vs. acute vs. chronic myocarditis, T2 myocardium (msec): 48 ± 3 vs. 59 ± 9 vs. 53 ± 5, p < 0.0001). Compared to controls, T2 values in remote myocardium were significantly different for acute myocarditis only , whereas T2 values in involved myocardium differed between all groups  and with native T1 .We demonstrate that quantitative T2 values are increased in patients with myocarditis. We further demonstrate that average mSAX and involved T2 values can discriminate between acute and chronic stage of the disease.We would like to acknowledge Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital National Health Service Foundation Trust. Dr. Rocio Hinojar was supported by the Spanish Society of Cardiology.


Background: Low-dose dobutamine stress echocardiography is increasingly used for identifying myocardial viability.Aim: We explored whether dobutamine-induced strain (S) and strain rate (SR) can identify myocardial viability following fibrinolytic therapy for ST-segment-elevation myocardial infarction (STEMI), taking 99mTc-sestamibi scintigraphy as the “gold standard” for diagnosis.Methods: We enrolled 60 consecutive patients presenting for myocardial viability assessment at least 4 weeks following STEMI. S and SR were measured by tissue Doppler imaging individually for all myocardial segments under low-dose dobutamine stress echocardiography. Patients underwent resting 99mTc-sestamibi scintigraphy using the standard imaging technique. Based on the results of 99mTc-sestamibi scintigraphy, the dobutamine-induced S and SR were compared between viable and non-viable segments. Receiver-operating characteristics curve was constructed to determine the cutoff value of the dobutamine-induced S and SR that best identifies viability.Results: The dobutamine-induced S and SR were significantly higher in viable compared with non-viable segments, a finding that was consistent for most individual myocardial segments (10 out of 16 for S and 11 out of 16 for SR). A cutoff value ranging from −8.5 to −9.6% for the S identified viability in apical and mid- segments, whereas a cutoff value ranging from −11.5 to −21.5% identified viability in basal segments. Similarly, a cutoff value ranging from −0.5 to −1.2 s−1 for the SR identified viability in apical and mid-segments, whereas a cutoff value ranging from −1.4 to −1.7/s−1 identified viability in basal segments.Conclusion: In patients undergoing viability assessment following fibrinolytic therapy for STEMI, the dobutamine-induced S and SR were higher in viable versus non-viable segments. A cutoff value of dobutamine-induced S and SR identified viability in most individual myocardial segments. Identification of viable myocardium following acute myocardial infarction has gained crucial importance with the recent step-up in myocardial revascularization techniques. The amount of viable myocardium is a “surrogate” of future improvement of left ventricular systolic function: the most powerful single predictor of long-term prognosis . Traditi99mTc-sestamibi scintigraphy as the “gold standard” for diagnosis.Low-dose dobutamine stress echocardiography (DSE) is well-acknowledged for identifying viable myocardium. Dobutamine-induced wall motion improvement is specific for predicting reversible contractile dysfunction; however, its sensitivity is suboptimal . Yet, thProspectively, we enrolled 60 consecutive patients who presented to our nuclear cardiology unit for myocardial viability assessment, at least 4 weeks following ST-segment-elevation myocardial infarction, during the period from May 2012 to May 2013. All patients had received fibrinolytic therapy , that started within 12 h of the onset of chest pain. Patients were considered eligible for inclusion if they had regional wall motion abnormality in the anatomical distribution of the infarct zone as detected by resting 2-D echocardiography. We excluded patients with early post-infarction unstable angina or severe hemodynamic instability, clinically evident congestive heart failure, significant valvular or congenital heart disease, any myocardial disease apart from ischemia, atrial fibrillation, bundle branch block, and technically inadequate echocardiographic imaging defined as more than two non-analyzable segments in the infarct zone. Similarly, we excluded from analysis segments with poor stain or strain rate signal . Before inclusion, informed written consent was obtained from each patient after full explanation of the study protocol. Finally, the study protocol was reviewed and approved by the institutional Human Research Committee, as it conforms to the ethical guidelines of the 1964 Declaration of Helsinki, as revised in 2013.Assessment of regional and global left ventricular systolic function was performed by trans-thoracic echocardiography, using a General Electric Vivid 7 Pro cardiac ultrasound machine  equipped with harmonic imaging capabilities. A 3.5 MHz phased-array transducer was used to obtain standard 2-D, M-mode, Doppler flow, and TDI. Patients were examined in the left lateral recumbent position using standard parasternal and apical views. Global left ventricular systolic function was assessed in apical 2- and 4-chamber views using the biplane Simpson’s method. Regional wall motion was assessed according to the standard 16-segment model recommended by the American Society of Echocardiography  was infused intravenously starting at 5 μg/kg/min, increased up to 20 μg/kg/min in 3-min stages. Standard views were recorded at baseline, as well as at the end of the infusion protocol. Images were digitized in cine-loop format and saved for subsequent playback and analysis. Views were analyzed offline by a single observer (Mohamed Ismail) employing the software program of the echocardiography machine . Systolic S and SR measurements were performed individually for each segment, both at baseline and at the end of dobutamine infusion  was administered by the oral route the day before the study , and 1 h before performing the study (60 mg single dose). Sublingual nitroglycerin 0.8 mg was administered in two divided doses with a 5-min interval just before radioactive tracer administration. The second dose was not given if the heart rate increased by 10 beats/min or more, or the systolic blood pressure decreased by 10 mm Hg or more after the first dose. Injection of 20–25 mCi of radioactive tracer was performed 45–60 min before SPECT image acquisition. Images were acquired using a rotating single-head gamma camera  equipped with low-energy all-purpose collimators. Energy windows of 20% were respectively centered on the 140-keV peaks of 99mTc-sestamibi. Thirty-two images were obtained over 180° extending from the 45° right anterior oblique to the 45° left posterior oblique projections, using a 64 × 64 acquisition matrix. All studies were subjected to quality-control checks and corrections when necessary for camera non-uniformity, center-of-rotation offsets, patient motion, and “upward creep.”Patients underwent resting 99mTc-sestamibi uptake was scored using the 5-point Scoring System as follows:0 = normal uptake,1 = mildly reduced uptake,2 = moderately reduced uptake,3 = severely reduced uptake,4 = absent uptake.Two experienced nuclear cardiologists blinded for both clinical and TDI data analyzed the scintigraphy images. Trans-axial reconstruction was performed using the standard back projection technique with a Ramp-Hanning filter. The reconstructed tomographic slices were 6 mm thick and reoriented along the short, horizontal long-, and vertical long-axis for interpretation. The vascular assignment of myocardial segments to the conventional anatomic distribution of major coronary arteries was performed according to the 17-segment Scoring System . Images Patterns of viability were based on the segmental radioactive tracer uptake so that segments were then individually classified into viable or non-viable. Score of 0 was considered as normal; 1 and 2 as viable; 3 and 4 as non-viable.t-test. Eventually, we generated receiver-operating characteristics curve to identify the cutoff value of the dobutamine-induced S and SR that best discriminates viable from non-viable myocardial segments based on 99mTc-sestamibi scintigraphy. The optimal cutoff value was defined as the value giving the largest area under the curve. Finally, ten cases were randomly selected for analysis of intra-observer variability of repeated measurement by the single observer. Assessment of variability was performed using linear regression. All analyses were two-sided and a probability value of p < 0.05 was considered statistically significant. Analyses were performed with SPSS version 12.0 statistical package .Continuous variables were presented as mean ± SD, if they were normally distributed. Data were tested for normal distribution using the Kolmogorov–Smirnov test. Categorical variables were described with absolute and relative (%) frequencies. According to the above assignment of myocardial segments, dobutamine-induced S and SR values were compared between viable and non-viable groups in each individual anatomical segment by means of the unpaired 99mTc-sestamibi scintigraphy image analysis was feasible in all segments.A total of 60 consecutive patients presenting at least 4 weeks following ST-segment-elevation myocardial infarction were enrolled in the current study. Baseline characteristics of the study cohort are presented in Table p  < 0.05 for all)   Table . Similarl) Table .99mTc-sestamibi scintigraphy as the “gold standard” for diagnosis, a cutoff value ranging from –8.5 to –9.6% for the S identified viability in apical and mid- segments, whereas a cutoff value ranging from –11.5 to –21.5% identified viability in basal segments  for the S, and r = 0.93  for the SR.The DSE protocol was well-tolerated by all patients with no major side effects during or after the test. The intra-class correlation between repeated measurements by the single observer (M.I.) was The current study demonstrated that in patients undergoing viability assessment following fibrinolytic therapy for ST-segment-elevation myocardial infarction, the dobutamine-induced S and SR were significantly higher in viable segments, compared with non-viable ones, a finding that was consistent for most individual myocardial segments (10 out of 16 for S and 11 out of 16 for SR).DSE is known to be operator-dependent; and therefore, liable for high inter- and intra-observer variability. Nevertheless, being feasible, safe, and inexpensive, with a fairly high diagnostic and prognostic accuracy, low-dose DSE is widely acknowledged for evaluation of viability following myocardial infarction. In the quest to overcome the subjective visual assessment of regional contractility, a good body of research has rigorously pursued to adopt quantitative measures of regional myocardial function during low-dose DSE. Although appealing at the outset, TDI-derived systolic tissue velocity was reportedly overwhelmed by “tethering” effect from neighboring segments, as well as by whole heart translation movement . RecentlGoing a step further, we explored the theme of “which level” of dobutamine-induced S and SR would identify viability in individual myocardial segments. In this sense – and to the best of the authors’ knowledge – the current study was the first to identify cutoff values of the dobutamine-induced S and SR that best recognize the viable segments on individual segment basis. Moreover, our results serve to support the results obtained by the prior studies, adding more strength to the “level of evidence.” Unfortunately, however, the results were somewhat inconsistent; favorable for many segments, but disappointing for some. The lack of consistency of the results in both S and SR might be attributed to angle dependency, a well-known downside of the strain imaging technique. Failure to keep the angle between the Doppler beam and the longitudinal shortening direction of the segment below 30° may have precluded accurate measurement of S and SR in some segments.We adopted measurement of TDI-based S and SR for assessment of myocardial viability by low-dose DSE. TDI-based measures have been constrained by susceptibility to signal noise and dependence on the angle of insonation . The rec99mTc-sestamibi scintigraphy as the “gold standard” for diagnosis of viability, we sought to improve its diagnostic accuracy. Thus, we employed a test protocol that entails the administration of both trimetazidine and nitroglycerin before radiotracer injection. A recent study by Feola et al. showed that the addition of trimetazidine to 99mTc-tetrofosmin scintigraphy improved the sensitivity of the perfusion scan for the detection of viable myocardial tissue, both at 2- and 6-months follow-up, compared with placebo, maintaining a satisfactory specificity  (Since we adopted cificity . Furtherctively) .In many centers, low-dose DSE remains the mainstay for detection of myocardial viability. Identification of viability following myocardial infarction is of paramount importance for the decision to triage patients for revascularization procedures. Nevertheless, the problems of needed expertise and lack of reproducibility have always put low-dose DSE under intense scrutiny. In a trial to improve the credibility of the widely popular test for viability detection, an “objective” way of assessment is eagerly needed. In this context, measurement of myocardial deformation indices during low-dose DSE would offer a substantial upgrading for the test. Moreover, the identification of cutoff values for the dobutamine-induced S and SR for the individual myocardial segments would further present a palatable easy-to-perform way to discriminate myocardial segments whose function will “recover” following revascularization. Going this way, low-dose DSE would potentially become the “standard of care” for viability detection in a not-too-distant future.99mTc-sestamibi scintigraphy as the “gold standard” for diagnosis of viability. Actual improvement of myocardial segment contractility following revascularization would offer a more “real” gold standard for comparison.Our findings were based on a single center study with a relatively small sample size of the cohort, a fact that makes it difficult to generalize our results to all patients undergoing viability assessment. Multicenter studies using the same protocol and examining a larger number of patients are needed. Additionally, the current technology of SR imaging is characterized by considerable noise in the SR signal. This noise increases further with higher heart rates and reduces image quality. Another limitation of the technique is the angle-dependency, which makes determination of S and SR in some segments less accurate. The adoption of a frame rate above 140 frames/s is another limitation. Furthermore, ECG tracking was used to detect systolic time rather than aortic valve opening and closure which is more accurate. Another limitation is that all patients received fibrinolytic therapy, and none of the patients was treated by primary percutaneous coronary intervention. It would be of interest to see if primary percutaneous coronary intervention shows greater viability in myocardial segments compared with fibrinolysis. Finally, we adopted In patients undergoing viability assessment following fibrinolytic therapy for ST-segment-elevation myocardial infarction, the dobutamine-induced S and SR were higher in viable compared with non-viable segments. A cutoff value of dobutamine-induced S and SR identified viability in most individual myocardial segments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The second study derived improved diastolic myocardial material parameters using in vivo MRI data from five normal human subjects. We combined these models to simulate ischemic mitral regurgitation by computationally infarcting an LV region including the posterior papillary muscle. Contact between our novel device and the mitral valve apparatus was simulated using Dassault Systèmes SIMULIA software. Incorporating improved cardiac geometry and diastolic myocardial material properties in the HCFS resulted in a realistic LV ejection fraction of 55%. Simulating infarction of posterior papillary muscle caused regurgitant mitral valve mechanics. Implementation of our novel device corrected valve dysfunction. Improvements in the current study to the HCFS permit increasingly accurate study of myocardial mechanics. The first application of this simulator to abnormal human cardiac function suggests that our novel annuloplasty ring with a sub-valvular element will correct ischemic mitral regurgitation.Ischemic mitral regurgitation is associated with substantial risk of death. We sought to: (1) detail significant recent improvements to the Dassault Systèmes human cardiac function simulator (HCFS); (2) use the HCFS to simulate normal cardiac function as well as pathologic function in the setting of posterior left ventricular (LV) papillary muscle infarction; and (3) debut our novel device for correction of ischemic mitral regurgitation. We synthesized two recent studies of human myocardial mechanics. The first study presented the robust and integrative finite element HCFS. Its primary limitation was its poor diastolic performance with an LV ejection fraction below 20% caused by overly stiffThe online version of this article (doi:10.1007/s13239-015-0216-z) contains supplementary material, which is available to authorized users. Ischemic mitral regurgitation is a consequence of adverse left ventricular (LV) remodeling after myocardial injury, in which there is enlargement of the LV chamber and mitral annulus, apical and lateral migration of the papillary muscles, leaflet tethering, and reduced coaptation area. These processes lead to malcoapation of the leaflets and consequently mitral insufficiency. The leaflets themselves are normal, and the disease occurs in the myocardium rather than in the valve itself.in vivo.Computational modeling is one way to systematically assess the effects of pathology and proposed surgical repair on heart function.In this invited article concerned with mitral valve function, pathology and therapeutic options, we therefore seek to: (1) detail our significant improvements in the geometry and diastolic material properties of the Dassault Systèmes HCFS; (2) use the resulting more realistic model to simulate normal cardiac function as well as abnormal cardiac function due to a myocardial infarction that includes the posterior LV papillary muscle; and (3) use the abnormal human heart model to debut a novel annuloplasty ring with a sub-valvular element for correction of ischemic mitral regurgitation.et al.We refer the interested reader to Sect. The Solid Zygote 3D Heart geometries for computer-aided design (CAD) and simulation were created by Zygote Media Group, Inc. . Generation I of the Solid Zygote Heart geometry  caused LV ejection fraction to increase from 19% to a more physiological value of 55%. Second, simulating infarction of the posterior LV papillary muscle caused regurgitant mitral valve mechanics; a pathologic state associated with a substantial risk of death.et al.et al.,The most effective surgical approach for treating severe ischemic mitral regurgitation remains controversial.et al.in vivo clinical or experimental data predict cardiac mechanics more realistically than those directly measured from ex vivo experimental data.Ours is the second study to be performed as part of the Living Heart Project. The first, ex vivo ovine mitral apparatus. Their LV model was based on MRI data from a sheep that developed moderate ischemic mitral regurgitation after postero-basal myocardial infarction. They demonstrated the utility and power of their finite element model by using it to test the hypothesis that a reduction in the stiffness of the ischemic region will decrease dyskinesis of the posterior LV wall, increase the displacement of the posterior papillary muscle and thereby increase ischemic mitral regurgitation. However, in that study, the leaflets were not modeled to include contact, which resulted in spurious penetration of the anterior leaflet into the posterior leaflet. That limitation was corrected in a subsequent study of the effect of annuloplasty ring shape in ischemic mitral regurgitation.Ours is one of the few finite element modeling studies to include the mitral valve and the LV. The first finite element model of the LV with mitral valvein vitro system in which mitral valve function can be extensively assessed. Once fully validated, their FSI model can be used to explore and compare various types of valvular pathology and repair. The long-term goal of their research is to provide an advanced FSI model of the mitral valve that could ultimately be used for individualized patient planning for mitral valve repair.In our study, we made significant improvements in cardiac geometry and diastolic myocardial material properties in the Dassault Systèmes HCFS. Opportunity for added realism in the HCFS remains, however. Our ultimate goal is to replace the compartment approach to the fluids portion of the simulation with a resolved 3D fluid dynamics solution. A fully coupled fluid–structure interaction (FSI) model of the human heart is highly desirable, albeit hugely challenging, and the major focus of research for numerous investigators. Kunzelman and co-workersIncluding flow analysis like that mentioned above would allow us to predict shear stresses on the myocardial wall, and more importantly, on the four heart valves, through the entire cardiac cycle. Such an approach presents tremendous opportunities to better understand the mechanisms of valvular disease and optimize treatment in the form of valve repair or replacement, either through open heart surgery or minimally invasive intervention. Despite the limited treatment of fluids in the current analysis, we are confident that our novel annuloplasty ring with a sub-valvular element will provide durable correction of ischemic mitral regurgitation because of (unpublished) promising long-term outcomes data from treated sheep.This study incorporated improved cardiac geometry and diastolic myocardial material properties in the Dassault Systèmes HCFS, which resulted in a realistic LV ejection fraction of 55%. Simulating infarction of the posterior LV papillary muscle predicted regurgitant mitral valve mechanics. Use of our undersized annuloplasty ring that included a sub-valvular element corrected valve dysfunction. Our experience suggests that valve repair can be further optimized with additional software  to develop novel annuloplasty rings with sub-valvular elements for correction of ischemic mitral or tricuspid regurgitation.Supplementary material 1 (MPG 1164 kb)Supplementary material 2 (MPG 1162 kb)Supplementary material 3 (MPG 1214 kb)Below is the link to the electronic supplementary material.


Cushing's disease (CD) has demonstrated subclinical myocardial involvement such as left ventricular (LV) hypertrophy and both diastolic and systolic impairment. Although myocardial fibrosis may play an important role in such myocardial alterations, the new T1 mapping techniques have not yet been used in CD to characterize the myocardium at baseline and to evaluate the effect of treatment on myocardial T1 values.This is a longitudinal pilot study performed in an academic center from Sept 2009 to Jan 2013. Ten consecutive patients  with active CD were included and matched with ten healthy volunteers  on age, sex and heart rate. Inclusion criteria were: age between 15 and 60 years and newly diagnosed and untreated CD. Subjects had a cardiac MRI exam shortly after diagnosis and a follow-up exam on average 6 month after cortisol normalization. Imaging protocol included MOLLI T1 mapping sequences before and after contrast injection and late gadolinium enhancement (LGE) 10 minutes after contrast injection. Average T1 values from an entire mid-ventricular slice were recorded for each patient before and after treatment and presence of LGE was visually noted.While no significant differences were noted between patients and controls in terms of BMI (p=0.08), significantly higher systolic and diastolic pressures were observed in CD . No patient had LGE.Before cortisol normalization, native myocardial T1 was increased in CD patients, as compared to controls . T1 values 15 minutes after enhancement were not significantly increased. After treatment, native T1 decreased markedly  becoming even lower than controls (p=0.009). T1 value after injection decreased significantly (respectively (p=0.039) in CD patients, reaching values significantly lower than those of controls (p=0.005). These findings favor the hypothesis of differential resolution of edema, interstitial fibrosis induced by CD and steatosis caused by metabolic syndrome which seems to persist.Before treatment, left ventricular ejection fraction was decreased in patients (p<0.028) and left ventricular mass was increased (p=0.076). After treatment, both parameters tended to normalize without reaching statistical significance.The drastic reduction in T1 values after treatment highlight the complexity of myocardial changes and the potential role of other confounders affecting T1 such as water and fat content. T1 after injection need further investigation. Native myocardial T1 is a potential tool to detect myocardial involvement in CD and in its follow-up treatmentN/A.