Understanding the interaction between the valves and walls of the heart is important in assessing and subsequently treating heart dysfunction. This study presents an integrated model of the mitral valve (MV) coupled to the left ventricle (LV), with the geometry derived from in vivo clinical magnetic resonance images. Numerical simulations using this coupled MV-LV model are developed using an immersed boundary/finite element method. The model incorporates detailed valvular features, left ventricular contraction, nonlinear soft tissue mechanics, and fluid-mediated interactions between the MV and LV wall. We use the model to simulate cardiac function from diastole to systole. Numerically predicted LV pump function agrees well with in vivo data of the imaged healthy volunteer, including the peak aortic flow rate, the systolic ejection duration, and the LV ejection fraction. In vivo MV dynamics are qualitatively captured. We further demonstrate that the diastolic filling pressure increases significantly with impaired myocardial active relaxation to maintain a normal cardiac output. This is consistent with clinical observations. The coupled model has the potential to advance our fundamental knowledge of mechanisms underlying MV-LV interaction, and help in risk stratification and optimisation of therapies for heart diseases. MV dysfunction remains a major medical problem because of its close link to cardiac dysfunction leading to morbidity and premature mortality .Computational modelling for understanding MV mechanics promises more effective MV repairs and replacement –5. BiomeBecause of the complex interactions between the MV, the sub-mitral apparatus, the heart walls, and the associated blood flow, very few modelling studies have been carried out that integrate the MV and ventricles in a single model –17. KunzLiving Heart project [Wenk et al.  reported project , which i project , HoweverThe earliest valve-heart coupling model that includes FSI is credited to Peskin and McQueen’s pioneering work in the 1970s –34 usingThis study reports an integrated MV-LV FSI model derived from in vivo images of a healthy volunteer. Although some simplifications are made, this is the first three-dimensional FSI MV-LV model that includes MV dynamics, LV contraction, and experimentally constrained descriptions of nonlinear soft tissue mechanics. This work is built on our previous models of the MV ,25 and L2.2.1.2; field of view: 302 × 400mm2; frame rate: 25 per cardiac cycle. Short-axis cine images covered the LV region from the basal plane to the apex, with slice thickness: 7 mm with 3 mm gap; in-plane pixel size: 1.3 × 1.3 mm2; frame rate: 25 per cardiac cycle.A cardiac magnetic resonance (CMR) study was performed on a healthy volunteer . The study was approved by the local NHS Research Ethics Committee, and written informed consent was obtained before the CMR scan. Twelve imaging planes along the LV outflow tract (LVOT) view were imaged to cover the whole MV region shown in The MV geometry was reconstructed from LVOT MV cine images at early-diastole, just after the MV opens. The leaflet boundaries were manually delineated from MR images, as shown in f, s, n) system. A rule-based method was used to construct the myofibre orientation within the LV wall. The myofibre angle was assumed to rotate from −60° to 60° from endocardium to epicardium, represented by the red arrows in The MV model was mounted into the inflow tract of the LV model according to the relative positions derived from the MR images in 2.2.x =  ∈ Ω, and the Lagrangian reference coordinate system is X =  ∈ U. The exterior unit normal along ∂U is N(X). Let χ denote the physical position of any material point X at time t, so that χ  = Ωs (t) is the physical region occupied by the immersed structure. The IB/FE formulation of the FSI system readsρ is the fluid density, μ is the fluid viscosity, u is the Eulerian velocity, p is the Eulerian pressure, and fs is the Eulerian elastic force density, which is determined from the deformed immersed structure and its active contraction. Note the IB formulation employs a common momentum equation for both the fluid and the solid, in which the additional solid stresses are accounted for by fs in x)[fs is determined from the first Piola-Kirchoff stress tensor The coupled MV-LV model employs an Eulerian description for the blood, which is modelled as a viscous incompressible fluid, along with a Lagrangian description for the structure. The fixed physical coordinates are  fs in x), in Eqs. fs in x), here th2.3.σ) in the coupled MV-LV system isσf is the fluid-like stress tensor, defined asσs is the solid stress tensor obtained from the nonlinear soft tissue constitutive laws. The first Piola-Kirchhoff stress tensor σs throughThe total Cauchy stress WmyT is the active tension described by the myofilament model of Niederer et al. [2+), sarcomere length, and the active tension at the resting sarcomere length (Treq).The myocardial active stress is defined asr et al. , using aTreq is set to 225 kPa to match the contractions observed in the imaged volunteer.The constitutive parameters in 2.4.2+ transient [Because only the myocardium below the LV basal plane contracts, we fix the LV basal plane along the circumferential and longitudinal displacements, but allow the radial expansion. The myocardium below the LV basal plane is left free to move. The valvular region is assumed to be much softer than the LV region. In diastole, a maximum displacement of 6 mm is allowed in the valvular region using a tethering force. In systole, the valve region is gradually pulled back to the original position. The inflow and outflow tracts are fixed. Because the MV annulus ring is attached to a housing structure which is fixed, no additional boundary conditions are applied to the MV annulus ring. Fluid boundary conditions are applied to the top planes of the inflow and outflow tracts. The function of the aortic valve is simply modelled as: the aortic valve is either fully opened or fully closed, determined by the pressure difference between the values inside the LV chamber and the aorta. After end-diastole, the LV region will contract simultaneously triggered by a spatially homogeneously prescribed intracellular Caransient , as showDiastolic filling: A linearly ramped pressure from 0 to a population-based end-diastolic pressure (EDP=8 mmHg) is applied to the inflow tract over 0.8 s, which is slightly longer than the actual diastolic duration of the imaged volunteer (0.6 s). In diastole about 80% of diastolic filling volume is due to the “sucking” effect of the left ventricle in early-diastole [Pendo, which is linearly ramped from 0 to 12 mmHg over 0.4 s, and then linearly decreased to zero at end-diastole. The value of Pendo is chosen by matching the simulated end-diastolic volume to the measured data from CMR images. Blood flow is not allowed to move out of the LV cavity through the inflow tract in diastole. Zero flow boundary conditions are applied to the top plane of the outflow tract.diastole . This neIso-volumetric contraction: Along the top plane of the inflow tract, the EDP loading is maintained, and the flow is controlled by the MV leaflet dynamics. Note during the iso-volumetric contraction, regurgitation may occur due to the MV closure action and the dysfunction of the MV apparatus. However, a small backflow before the MV is fully closed may be deemed normal [d normal . Zero flSystolic ejection: When the aortic valve opens, a three-element Windkessl model is coupled to the top plane of the outflow tract to provide afterload. The volumetric flow rates across the top plane of the outflow tract is calculated from the three-dimensional MV-LV model, and fed into the Windkessel model [el model , which rIso-volumetric relaxation: Zero flow boundary conditions are applied to both the top planes of the outflow and inflow tracts until the total cycle ends at 1.2 s.t0 = 1.22 × 10−4 s is used in the diastolic and relaxation phases, a reduced time step size (0.25 Δt0) is used in the early systole with a duration of 0.1 s, and an even smaller time step of 0.125 Δt0 is used in the remainder of the systolic phase. Because explicit time stepping is used in the numerical simulations [The coupled MV-LV model is immersed in a 17 cm × 16 cm × 16 cm fluid box. A basic time step size Δulations , we needhttps://github.com/IBAMR/IBAMR), which provides an adaptive and distributed-memory parallel implementation of the IB methods. IBAMR leverages functionality provided by other freely available software libraries, including SAMRAI (https://computation.llnl.gov/casc/SAMRAI), libMesh (https://libmesh.github.io), PETSc (http://www.mcs.anl.gov/petsc), and hypre (http://www.llnl.gov/CASC/hypre). All simulations were carried out on a Linux workstation at the University of Glasgow with 10 Intel(R) Xeon(R) CPU cores (2.65 GHz) and 32 GB RAM. The simulation time for one cardiac cycle is around 240 h (10 days).The MV-LV model is implemented using the open-source IBAMR software framework , the central LV pressure is negative, and the associated diastolic filling volume is around 65 mL, which is 90% of the total diastolic filling volume. In late-diastole, the LV pressure becomes positive. There is a delay between the myocardial active tension and the intracellular Ca2+ profile, but the central LV pressure follows the active tension closely throughout the cycle as shown in3.2.3.3.The LV systolic strain related to end-diastole is shown in 3.4.endo) creates a negative pressure inside the LV chamber, similar to the effects of the myocardial active relaxation. We further investigate how Pendo affects the MV-LV dynamics by varying its value from 8 mmHg to 16 mmHg, and the effects without Pendo but with an increased EDP from 8 mmHg to 20 mmHg. We observe that with an increased Pendo, the peak flow rate across the MV during the filling phase becomes higher with more ejected volume through the aortic valve. We also have a longer ejection duration, shorter iso-volumetric contraction time, and higher ejection fraction as a result of increasing Pendo. On the other hand, if we do not apply Pendo, a much greater and non-physiological EDP is needed for the required ejection fraction. For example, with EDP=8 mmHg, the ejection fraction is only 29%. Only when EDP=20 mmHg, the pump function is comparable to the case with EDP=8 mmHg and Pendo = 16 mmHg. These results are summarised in From 4.This study demonstrates the feasibility of integrating a MV model with a LV model from a healthy volunteer based on in vivo CMR images. This is the first physiologically based MV-LV model with fluid-structure interaction that includes nonlinear hyperelastic constitutive modelling of the soft tissue. The coupled MV-LV model is used to simulate MV dynamics, LV wall deformation, myocardial active contraction, as well as intraventricular flow. The modelling results are in reasonable quantitative agreement with in vivo measurements and clinical observations, such as the peak aortic flow rate (468mL/s vs. 498mL/s), the ejection duration (243 ms vs. 300 ms), peak cuff-measured systolic pressure (162 mmHg vs. 150 mmHg), and LV ejection fraction (51% vs. 57%). Note that the above comparisons are made with computational vs. imaged values.Pendo. Specifically, we can enhance or suppress the myocardial relaxation by adjusting Pendo. Our results in Pendo ≥ 12 mmHg, there is more filling during diastole, compared to the cases when Pendo < 12 mmHg under the same EDP. This in turn gives rise to higher ejection fraction and stroke volume. However, if myocardial relaxation is suppressed, diastolic filling is less efficient, with subsequently smaller ejection fraction and stroke volume. In the extreme case, when the myocardial relaxation is entirely absent, chamber volume increases by only 29.5 mL, and ejection fraction decreases to 29%. To maintain stroke volume obtained for Pendo=12 mmHg, EDP needs to be as high as 20 mmHg. Indeed, increased EDP resulted from an impaired myocardial relaxation has been reported in a clinical study by Zile et al. [Diastolic heart failure is usually associated with impaired myocardial relaxation and increased filling pressure ,48. In tPendo, the peak flow rate (200mL/s) is much less than the measured value. One reason is because of the extra resistance from the LV wall, which is absent in the MV-tube model [During diastole, the MV-LV model seems to yield a smaller orifice compared to the corresponding CMR images. In our previous study , the MV be model . The diabe model : the rapμCT experiments, Toma et al. [In a series of studies based on in vitro a et al. ,26,27 suSeveral other limitations in the model may also contribute to the discrepancies. These include the uncertainty of patient-specific parameter identification, the uncertainty in MV geometry reconstruction from CMR images, the passive response assumption around the annulus ring and the valvular region of the LV model, and the lack of pre-strain effects. Studies addressing these issues are already under way. We expect that further improvement in personalised modelling and more efficient high performance computing would make the modelling more physiologically detailed yet fast enough for applications in risk stratification and optimisation of therapies in heart diseases.5.Interaction between the mitral valve and the ventricular wall plays an essential role in cardiac pump function. In this study, we have developed a first fully coupled MV-LV model that includes fluid-structure interaction as well as soft tissue mechanics with model parameters determined from in vivo image data. The model geometry is derived from in vivo magnetic resonance images of a healthy volunteer, and incorporates three-dimensional finite element representations of the MV leaflets, sub-valvular apparatus, and the LV geometry. Fibre-reinforced hyperelastic constitutive laws are used to describe the passive response of the soft tissues, and a myofilament model is used to model the myocardial active contraction. Our results show that the developed MV-LV model can simulate MV-LV interaction with good agreements, including the peak aortic flow rate, the peak systemic pressure, the systolic ejection duration and the LV ejection fraction, with in vivo measurements despite several modelling limitations. We further find that with impaired myocardial active relaxation, the diastolic filling pressure needs to increase significantly in order to maintain a normal cardiac output, which is consistent with clinical observations in patients with impaired myocardial relaxation. This model thereby represents a step towards a whole-heart multiphysics modelling with a target for clinical applications.


The purpose of this research was to assess the feasibility of reconstructing the middle hepatic vein (MHV) with resected left portal vein during left hemihepatectomy.From January 2014 to January 2018, six patients received left hemihepatectomy combined with MHV reconstruction using the resected left portal vein in West China Hospital. We reviewed the clinical data including patient details, surgical technique, graft patency, and operative results.All six patients underwent left hemihepatectomy for liver tumors located at left hepatocaval confluence. In these patients, MHV was resected due to tumor invading and reconstructed using the resected left portal vein as graft. The mean operating time was 316 min. Two patients developed complications: one experienced bile leakage and one experienced pleural effusion. No patient developed vascular graft complications. All the grafts remained unobstructed, and no local tumor recurrence occurred during the observation period of 13–41 months.Our results indicated that the left portal vein was a safe graft for hepatic vein reconstruction. In addition, left hemihepatectomy combined with middle hepatic vein resection and reconstruction using the left portal vein can be performed safely to treat liver tumors located at hepatocaval confluence. In recent years, advances in surgical technology have resulted in a great improvement in the survival time of patients who underwent curative liver resection. Due to the invasion of liver tumors, there are a large number of patients that can only be cured with liver resection combined with hepatic vein resection. When the tumor infiltration range is small, a patch reconstruction or primary closure of the hepatic vein is performed. Whereas when the tumor has a wide range of infiltration, hepatic vein reconstruction using a graft is required to prevent vascular stenosis . There hIn this research, we retrospectively analyzed the clinical data of six patients who underwent left hemihepatectomy for liver tumors located at left hepatocaval confluence. In these patients, MHV was resected due to tumor invasion and reconstructed using the left portal vein.From January 2014 to January 2018, 4600 patients underwent various types of hepatectomies at the West China Hospital. Six of these patients underwent left hemihepatectomy with MHV resection and subsequent reconstruction using the left portal vein. The patient characteristics are presented in Table Liver function and other routine examinations were performed after admission. Before liver resection, abdominal enhanced computed tomography (CT) scan or magnetic resonance imaging (MRI) was performed to assess the extent of the lesions, gross type, liver volume, and distant metastasis Fig. . Three-dOur preferred approach was the J-shaped subcostal incision. After freeing the perihepatic ligaments and adequately exposing the left lobe of the liver, we routinely used intraoperative ultrasound (US) to locate the boundaries of the tumor and assess its anatomical relationship with the surrounding important vessels. The liver parenchyma was transected using the Harmonic scalpel  or CUSA . The intermittent Pringle maneuver was applied to occlude hepatic flow for 20 min, followed by 5 min of liver reperfusion, circularly, until the tumor was completely removed. To obtain sufficient surgical margins, a 2- to 3-cm portion of tumor infiltration of the MHV was resected. During parenchyma transection, the dissected MHV was blocked by vascular clamps. Immediately after resecting the left liver, we isolated and harvested 3 cm of the left portal vein from the dissected liver to use as a graft  for aiming an optimal anticoagulant prophylaxis. After hospital discharge, the patients were treated with warfarin  for 3 months. Ultrasonography or enhanced abdominal CT was performed every month to confirm the patency of the reconstructed MHV in the first 3 months, and post-discharge follow-up studies were conducted at 2-month intervals after that  Comparing with artificial and allograft blood vessel, it does not increase the incidence of infection and rejection. (2) Comparing with autologous veins such as the great saphenous vein, it does not lead to additional trauma or vascular congestion. (3) The left branch of the portal vein is long enough, and its diameter is similar to that of the hepatic vein. (4) The structure of portal vein wall is similar to that of hepatic vein, with high tenacity. The disadvantages are as follows: (1) Removal of the left branch of the portal vein from resected specimens increases the risk of recurrence of liver tumor. (2) The left branch of the portal vein supplies the caudate lobe, so the graft has many branches which need repair. In this study, the operations went without any important complication but for small blood losses (the mean blood loss was 433 ml). The results showed that the technique could effectively reconstruct hepatic vein without increasing blood loss and surgical time. In these six patients, liver tumors locate at the left hepatocaval confluence, which is far from the portal vein. There is no tumor recurrence during the observation period of 13–41 months in all patients. Therefore, this technique should be performed in strictly selected patients. The indications of using the left branch of the portal vein as a graft for hepatic vein reconstruction are as follows: (1) The tumor is located in the second hepatic portal area and invades the middle hepatic vein or left hepatic vein. Therefore, left hepatectomy combined with reconstruction of the middle hepatic vein is needed. (2) The tumor is small in diameter and distant from the first hepatic portal area. (3) No portal vein invasion or portal vein tumor thrombus is found before surgery. This study has shown that the left branch of the portal vein is a perfect graft and this method can be used safely in patients with benign tumor and trauma.As far as we know, this study provides the first evidence of left portal vein grafts for major hepatic vein reconstruction in liver resection. Our results suggest that the portal vein is a safe graft and left hemihepatectomy combined with MHV reconstruction using a left portal vein graft can be performed resulting in a good prognosis in selected patients.


Radical cystectomy, which is a standard treatment of muscle invasive and high-grade non-invasive bladder tumour, is accompanied with high rates of postoperative complications including major adverse cardiac events (MACE). Diastolic dysfunction is associated with postoperative complications. We evaluated perioperative risk factors including diastolic dysfunction related with MACE within 6 months after radical cystectomy. The 546 patients who underwent elective radical cystectomy were included. Diastolic dysfunction was defined as early transmitral flow velocity (E)/early diastolic mitral annulus velocity (e′) > 15. Logistic regression analysis, Kaplan-Meier survival analysis and log-rank test were performed. MACE within 6 months after radical cystectomy developed in 43 (7.9%) patients. MACE was related with female  and diastolic dysfunction . The 6-month mortality were significantly higher in the MACE group, and hospital stay and intensive care unit stay were significantly longer in the MACE group compared to the non-MACE group. Accordingly, preoperative diastolic dysfunction (E/e′ > 15) was related with postoperative MACE and MACE was related with 6-month survival after radical cystectomy. These results suggest that preoperative diastolic dysfunction can provide useful information on postoperative complications. Radical cystectomy is classified as a major operative procedure and is accompanied with high postoperative complication rates among urological operations. High rates of morbidity after radical cystectomy is due to not only its technical challenges of the operation but also the characteristics of the patients with mostly elderly population with associated underlying comorbidities3. Even with considerable advances in surgical and anaesthetic techniques, early complication rates occurring within 90 days after radical cystectomy still ranges over 58–64%6. Among early complications after radical cystectomy, cardiac complications are reported at the range of 1.4–4.1% and significantly affect postoperative morbidity and mortality7.Radical cystectomy is regarded as a standard treatment in patients with muscle invasive and high-grade non-invasive bladder tumour8. In this regard, diastolic dysfunction may demonstrate on primary cardiac events9. The clinical implication of diastolic dysfunction may be particularly relevant in surgeries including mostly elderly patients such as radical cystectomy. However, the prognostic role of diastolic dysfunction as a preoperative risk factor of postoperative major adverse cardiac events (MACE) in patients undergoing radical cystectomy has not been clearly explained.Diastolic dysfunction presents diminished left ventricular compliance due to abnormal left ventricular relaxation and filling during diastole, and subsequently increased left ventricular filling pressure. Sustained increase in left ventricular filling pressure can be intolerable in volume adjustment and hence is associated with perioperative cardiac eventsTherefore, in the present study, we aimed to evaluate independent risk factors including diastolic dysfunction related with MACE within 6 months following radical cystectomy in bladder cancer patients. In addition, postoperative outcomes such as acute kidney injury, pulmonary complications, 6-month mortality, and lengths of intensive care unit stay and hospital stay were compared between MACE group (patients who developed MACE) and non-MACE group (those who did not).We analysed 546 patients who underwent radical cystectomy during the study period Fig. . We exclPatient characteristics, medications, clinical characteristics, laboratory data, and transthoracic echocardiography parameters of 546 patients are described in Table Univariate analysis showed that age, gender, diuretic, aspirin, vasodilator, E/e′ > 15, and urinary diversion type were associated with MACE within 6 months after radical cystectomy. After multivariate analysis, female  and E/e′ > 15  were related with MACE within 6 months after radical cystectomy  and female gender were related with MACE within 6 months after radical cystectomy in bladder cancer patients. Furthermore, postoperative MACE was related with 6-month survival after radical cystectomy.10. Although congestive heart failure includes both systolic and diastolic heart failure, clinical research has been relatively focused on systolic heart failure, and diastolic heart failure has not been thoroughly studied due to the lack of a universal, non-invasive classification method and meticulous approach in diagnosis12. Also, the correlation of preoperative diastolic dysfunction and postoperative MACE has not been well described after non-cardiac surgery. Significant portion of elderly patients undergoing cardiac or non-cardiac surgeries commonly show diastolic dysfunction with normal left ventricular ejection fraction, as ranging over 50% as reported by Phillip et al.13. Thus, the clinical implication of diastolic dysfunction may be particularly important in a type of surgery with extensive long operation duration with mostly elderly patients. Previous studies have evaluated diastolic dysfunction and MACE after non-cardiac surgery16. However, the present study has strength that we evaluated the relationship of diastolic dysfunction and postoperative MACE in a large number of homogeneous elderly patients undergoing high-risk non-cardiac surgery, which is radical cystectomy.The present study revealed that preoperative diastolic dysfunction was related with postoperative MACE after radical cystectomy. It is well acknowledged that a history of congestive heart failure is associated with higher risk of postoperative morbidity as well as mortality following non-cardiac surgery15. First, diastolic dysfunction can induce the increase in left ventricular filling pressure and the intolerance in volume adjustment, and subsequently poor cardiac outcomes17. Second, diastolic dysfunction may impair coronary flow18. Galderisi et al. have found that coronary flow reserve was reduced in subjects with diastolic dysfunction19. It was noted that increases in left ventricular wall stress in individuals with normal physiology increases the coronary flow reserve and subsequently increases myocardial blood flow20. However, this is often impaired in individuals under pathologic states such as left ventricular diastolic dysfunction, advanced age with possible cardiac structural abnormalities, or subclinical myocardial fibrosis22. In addition, tachycardia may aggravate coronary flow reduction in individuals with reduced coronary flow reserve18. Thus, our group of patients with increased E/e′ undergoing radical cystectomy, which need a large amount of intraoperative fluid administration, may be prone to coronary flow impairment followed with subendocardial ischaemia and hence have resulted in postoperative MACE. Third, inevitable volume depleting condition as well as volume loading condition from long operation time with substantial amount of blood loss may affect haemodynamic instability and left ventricular remodelling which may have also contributed to postoperative MACE after radical cystectomy.Preoperative diastolic dysfunction is reported to be associated with postoperative cardiac complications, particularly in the elderly and there may be following reasonset al. have reported significantly high rates of MACE in patients with baseline left ventricular ejection fraction <50% compared to normal left ventricular ejection fraction in patients undergoing transcatheter aortic valve implantation23. Also, left ventricular ejection fraction <50% was an independent predictor of MACE in elderly patients undergoing non-cardiac surgery24. However, most of the patients in our study had normal range of ejection fraction without evidence of heart failure. Therefore, in the present study, systolic heart failure was not found as a risk factor of MACE after radical cystectomy.Systolic heart failure is considered to be associated with MACE in several previous reports. Ewe 25. The incidence of cardiovascular events increases in post-menopause women; therefore, elderly women experience higher rate of cardiovascular events and mortality compared to age-matched men25. Considering that the patients in the present study had a mean age of 64 years, sex steroid hormone may have influenced the manifestation of MACE after radical cystectomy in the present study. In addition, several studies have reported gender-specific discrepancy after radical cystectomy, with female gender having poor postoperative outcomes compared to male gender27. It has been suggested that different pelvic anatomy renders the gender difference in disease progression and postoperative outcomes. Prostatic capsule and prostatic urethra may block the angio-lymphatic extension of cancer cell in male gender28. Also, since female bladder neck muscle is not as sturdy as male, lymphatic drainage pattern may have differed and hence influenced the gender-specific discrepancy.We found that female gender was also related with MACE within 6 months after radical cystectomy. There has been conventional view that sex steroid hormones exhibit different actions against cardiac stress, although the details on the mechanism of action are unresolvedet al. noted that postoperative MACE increased risk of mortality in patients undergoing non-cardiac surgery29. The authors suggested that perioperative myocardial injury cannot overcome the surgical stress, and inability to cope with the stress may have turned out as high mortality29. Furthermore, clinically silent troponin elevation from myocardial injury during postoperative period is known to increase the long-term mortality after major non-cardiac surgery30.Here, we have shown that post-operative MACE was significantly related with post-operative mortality. In line with the present study, Beattie 31. Also, there was no additional predictive value in the intra-individual variation of E/e′32. We therefore assumed that a single measurement of septal E/e′ can be used as a parameter of left ventricular filling pressure and hence be a predictive parameter of MACE after radical cystectomy.The present study has limitations stemming from its retrospective observational design, which is prone to selection bias. Moreover, as we only included patients who underwent preoperative transthoracic echocardiography, our findings need to be interpreted with caution prior to wider generalisation. Second, our results from the logistic regression analysis may have been limited by the relatively small number of patients with MACE. Third, the Doppler tissue imaging parameters to evaluate the diastolic dysfunction were limited. As for E/e′, a single measurement of septal mitral annular velocity was only attainable. However, it has been reported that there are no significant differences among E/e′ of septal mitral annular velocity, E/e′ of lateral mitral annular velocity, and the average of E/e′ in their predictive value for cardiac eventsIn conclusion, this study showed that preoperative diastolic dysfunction, which was evaluated by E/e′ > 15, was related with MACE within 6 months after radical cystectomy in patients who underwent preoperative transthoracic echocardiography. Postoperative MACE was related with 6-month survival after radical cystectomy. These results suggest that preoperative evaluation of left ventricular diastolic function with E/e′ may be helpful in predicting cardiac outcomes after radical cystectomy.The protocols of this study were approved by the Institutional Review Board of Asan Medical Center . We included patients who underwent elective radical cystectomy at our institution between November 2000 and December 2016. The demographic and clinical characteristics, laboratory data, and intraoperative and postoperative data were collected from digitized patient records  and the database at Asan Medical Center. We excluded patients who were below 20 years of age and had missing data. The requirement for written informed consents was waived by the Institutional Review Board due to retrospective study design. All methods were carried out in accordance with relevant guidelines and regulations.General anaesthesia was induced with either thiopental or propofol intravenous injection with rocuronium. Anaesthesia was maintained using volatile anaesthetic agents  with 50% oxygen/air mixture. Conventional parameters including electrocardiography, heart rate, peripheral oxygen saturation, and continuous arterial blood pressure were used for haemodynamic and fluid management. Core temperature was monitored by using oesophageal stethoscope.Crystalloid solutions  or lactated Ringer’s solution) and colloid solutions  or 5% albumin) were administered. Crystalloid solution was administered at a rate of 6–10 ml/kg/hr, and colloid solution was used at anaesthesiologist’s discretion. Packed red blood cells were transfused to maintain a haemoglobin concentration greater than 8 g/dL.34. Pelvic lymphadenectomy and radical cystectomy were carried out according to the standard technique used at our centre. Standard lymph node dissection including the external iliac, distal common iliac, obturator, hypogastric, and perivesical lymph nodes or extended lymph node dissection to the extent of the distal aorta, proximal common iliac artery, and vena cava was done as determined by the urologic surgeon. Subsequent urinary diversion of ileal neobladder or ileal conduit was carried out after determination of the type by the urologic surgeon.Surgical technique was performed as followsThe variables included patient characteristics , preoperative medications , clinical characteristics , preoperative laboratory values , preoperative transthoracic echocardiography parameters /late transmitral filling velocity (A), deceleration time, and left ventricular end-diastolic volume), intraoperative data , and postoperative data . The study period was divided into the past half period (period 1) and the recent half period (period 2) by the average of the period; Years 2005 to 2010 were classified as period 1 and years 2011 to 2016 were classified as period 2.Diabetes mellitus was defined as a history of uncontrolled blood glucose level with preoperative history of antihyperglycaemic medication. Hypertension was defined as systolic arterial blood pressure >140 mmHg and diastolic blood pressure >90 mmHg with preoperative history of antihypertensive medication. Hyperlipidaemia was defined as elevated serum lipoproteins or preoperative history of antihyperlipidemic medication. Heart failure was defined as left ventricular systolic dysfunction with ejection fraction less than 40%. Cerebrovascular disease was defined as a history of stroke, cerebral haemorrhage, or carotid artery stent or angioplasty. Coronary artery disease was defined as previous diagnosis of ischaemic heart disease by a cardiologist. Preoperative diuretic included thiazide, furosemide, and spironolactone. Preoperative vasodilator included isoket, nitroglycerine, and nitrate.35. Tumour grade was assessed by the 2016 World Health Organization grading system36. A portion of patients received neo-adjuvant or adjuvant chemotherapy according to the decision of surgeons and oncologists. Neo-adjuvant chemotherapy comprised the combinations of gemcitabine/cisplatin, methotrexate/vinblastine sulfate/cisplatin/doxorubicin, or gemcitabine/carboplatin. Adjuvant chemotherapy comprised the combinations of gemcitabine/cisplatin, methotrexate/vinblastine sulfate/cisplatin/doxorubicin, or cyclophosphamide/cisplatin.Tumour stage was assessed by the 2010 American Joint Committee on Cancer tumour-node-metastasis staging system37. Among various indices of indicating diastolic dysfunction, E/e′ is most widely used as a parameter of indicating left ventricular filling pressure38. We used E/e′ > 15 as the optimal cut off value since this best predicts increased left ventricular end-diastolic pressure39. Hypotensive episode was defined as mean arterial blood pressure below threshold of 60 mmHg with the duration of more than 5 minutes40. Vasopressor/inotropic such as phenylephrine, ephedrine, or norepinephrine was used when the hypotensive episode occurred.Preoperative transthoracic echocardiography was performed 2 months prior to surgery by experienced sonographers. Preoperative echocardiography was performed as determined by the attending anaesthesiologists and urologists. The parameters included left ventricular ejection fraction, E/e′, E/A, deceleration time, and left ventricular end-diastolic volume. The E and A were measured from the apical four-chamber view, and e′ was measured by pulsed wave Doppler with a sample volume from the septal site of the mitral annulus. Then, the E/e′ was calculated and used to determine increased left ventricular filling pressure41. Postoperative MACE was recorded if the patient had one of the following complications within 6 months after radical cystectomy; acute myocardial infarction, arrhythmia, heart failure, cerebrovascular accident, or nonfatal cardiac arrest. Acute myocardial infarction was defined as increase in troponin, serum cardiac marker with one of the ischaemic symptoms; newly significant ST segment or T wave changes on electrocardiogram, development of pathological Q wave on electrocardiogram, or echocardiographic evidence of new regional wall motion abnormality. Arrhythmia included atrial fibrillation, atrial flutter, or second- or third-degree atrioventricular conduction block. Heart failure included newly developed postoperative left ventricular systolic dysfunction with ejection fraction less than 40%. Cerebrovascular accident included transient ischaemic attack, stroke, or cerebral haemorrhagic events during postoperative period. Non-fatal cardiac arrest was defined as the absence of cardiac rhythm or chaotic rhythm requiring cardiac life support.Postoperative MACE was defined based on the European Perioperative Clinical Outcome definitions41. Postoperative acute kidney injury was defined as an increase in serum creatinine by ≥0.3 mg/dL within 2 days after surgery or an increase in serum creatinine to ≥1.5 times baseline within 7 days after surgery41. Postoperative pulmonary complications were defined as newly diagnosed acute lung injury or newly diagnosed respiratory infection with one or more of the following criteria: lung opacity, fever, new sputum, white blood cell count >12 × 103/μL, or newly detected pleural effusion demonstrated on chest radiograph during hospitalization after surgery41. Postoperative 6-month mortality was defined as all-cause mortality within 6 months after radical cystectomy.Acute kidney injury was defined by Kidney Disease Improving Global Outcomes (KDIGO) guidelinesContinuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as number (percentage). For comparison of demographics and intraoperative and postoperative characteristics between the MACE group and non-MACE group, chi-square test or the Fisher’s exact test was used for categorical variables and Mann-Whitney U test or the Student’s t-test was used for continuous variables.Univariate and multivariate logistic regression analyses were conducted to identify risk factors that were associated with MACE within 6 months after radical cystectomy. The most relevant factors associated with postoperative MACE were independently assessed in univariate logistic regression analysis and the variables with a P < 0.05 were assessed in the multivariable logistic regression analysis.P values were 2-sided, and those <0.05 were considered statistically significant. SPSS Version 23.0  was used for all data manipulations and statistical analyses.The Kaplan-Meier method was used to describe the distribution of survival time within 6 months after radical cystectomy. The log-rank test was performed to compare differences in survival rates of the MACE group and non-MACE group. All reported


Simple tricuspid valve surgery for complex heart disease with systemic right ventricular dysfunction is a high‐risk procedure; however, staged tricuspid valve surgery following cardiac resynchronization therapy seems to be a beneficial method to expect reverse systemic ventricular remodeling. Nevertheless, gradual advanced tricuspid regurgitation (TR) and systemic right ventricular (sRV) dysfunction remain the main contributors to mortality and disability in patients with ccTGA after adulthood.2The patient was a 31‐year‐old man with ccTGA, pulmonary artery stenosis, and TR associated with an Ebsteinoid valve diagnosed at the age of 1 month, who had not been followed up with since he was 23 years old. He was referred to our hospital because of syncope. His physical function was classified as New York Heart Association (NYHA) functional class III. Radiography revealed cardiomegaly  with pulmonary congestion. Electrocardiography revealed a complete atrioventricular block (CAVB) with a heart rate of 46 bpm and QRS duration of 122 ms and an unstable ventricular tachycardia (VT). His plasma brain natriuretic peptide (BNP) level was 494 pg/mL. Echocardiography revealed a dilated sRV end‐diastolic dimension (sRVDd) of 66 mm, diffuse hypokinesis, and severe TR  were still observed (Figure 2 and 41%‐44%, respectively, and a decrease in sRVEDVI from 120 to 88 mL/m2 (Figure At 3 years after CRT‐D implantation, the patient's NYHA classification was class II. The CTR on the chest radiography and the sRVDd on the echocardiography decreased from 66% to 56% and from 66 to 58 mm, respectively Figure . The dec3Tricuspid regurgitation, CAVB, and sRV failure are major complications in adult patients with ccTGA.We could safely administer the beta‐blocker, amiodarone, and ACE inhibitor owing to reverse tissue and electrical sRV remodeling after CRT‐D implantation. Our case showed reverse sRV remodeling twice: The first included reverse electrical remodeling after CRT‐D implantation,4Staged TVR after CRT is a valid option for rescuing a ccTGA patient with TR and sRV dysfunction. Further larger studies are required to establish the long‐term efficacy of this strategy in ccTGA.None declared.SA DT, HS, and MN: conceived and designed the study. SA and DT: acquired, analyzed, and interpreted the data. SA and DT: drafted the manuscript.


The need to simulate the operating conditions of the human body is a key factor in every study and engineering process of a bioengineering device developed for implantation. In the present paper, we describe in detail the interaction between the left ventricle (LV) and our Sputnik left ventricular assist devices (LVADs). This research aims to evaluate the influence of different rotary blood pumps (RBPs) on the LV depending on the degree of heart failure (HF), in order to investigate energetic characteristics of the LV-LVAD interaction and to estimate main parameters of left ventricular unloading. We investigate energetic characteristics of adult Sputnik 1 and Sputnik 2 LVADs connected to a hybrid adult mock circulation (HAMC) and also for the Sputnik pediatric rotary blood pump (PRBP) connected to a pediatric mock circulation (PMC). A major improvement of the LV unloading is observed during all simulations for each particular heart failure state when connected to the LVAD, with sequential pump speed increased within 5000–10000 rpm for adult LVADs and 6000–13000 rpm for PRBP with 200 rpm step. Additionally, it was found that depending on the degree of heart failure, LVADs influence the LV in different ways and a significant support level cannot be achieved without the aortic valve closure. Furthermore, this study expands the information on LV-LVAD interaction, which leads to the optimization of the RBP speed rate control in clinics for adult and pediatric patients suffering from heart failure. Finally, we show that the implementation of control algorithms using the modulation of the RBP speed in order to open the aortic valve and unload the LV more efficiently is necessary and will be content of further research. Nowadays, about 8 million people in Russia suffer from heart failure (HF), and among them, approximately 2.5 million have acute HF (classes III and IV of the New York Heart Association (NYHA) classification of heart failure), which tends to be the most widespread cause for hospitalization and lethal outcome of heart diseases –3.Left ventricular assist devices (LVADs) were designed as a therapeutic option to treat end stage HF patients in response to the large patient populations with acute HF along with limited number of donor hearts. Initially, LVADs were designed as pulsatile blood pumps to support or replace the native ventricle. Eventually, LVADs evolved to rotary blood pumps (RBPs) providing continuous flow to maintain temporary and permanent circulatory support , 5.Implantation of a LVAD leads to a dynamic interaction between the cardiovascular system and the LVAD, where the LVAD is unloading the ventricle via undertaking part of the load and in some cases causing its recovery. In its turn, the ventricle function influences the performance of the LVAD . In ordeInvestigation of in vitro dynamic of LVAD is of importance due to its influence on the LVAD patients' outcome. It has been shown that the introduction of energetic parameters could lead to improved cardiac mechanical efficiency . MoreoveThe clinical importance of pulsatility is a recurring topic of debate in mechanical circulatory support. Lack of pulsatility has been identified as a possible factor responsible for adverse events and has also demonstrated a role in myocardial perfusion and cardiac recovery. Moreover, additional benefits of pulsatile ventricular assist devices (VADs) over continuous-flow systems are the greater likelihood of aortic valve opening. Investigation on the dynamics and characteristics of the LVAD and the pulmonary artery pulsatile index is also of importance due to the possibility to predict the risk of the gastrointestinal bleeding in patients with LVAD . This isThe interaction between the left ventricle (LV) and the RBP can be examined via pressure-volume (P-V) diagram of the ventricle as the stroke work can be expressed by the area inside P-V diagram. In addition, dynamic head pressure-bypass flow (H-Q) curves of the pump are a strong tool for the evaluation of the LV-LVAD interaction, since dynamic H-Q curves describe RPB behavior during the cardiac cycle . Also, tIn this study, the interaction between different Sputnik LVADs and the LV with various degrees of HF was investigated. The evaluated LVADs are the adult Sputnik 1 and Sputnik 2, and furthermore, the Sputnik pediatric RBP (PRBP) was engineered for pediatric patients with a body weight between 12 and 40 kg. This research is aimed (i) to evaluate the Sputnik LVADs and Sputnik PRBP influence on the LV depending on the HF degree, (ii) to estimate main parameters of the LV unloading, (iii) to investigate energetic characteristics of the LV-LVAD interaction for the adult Sputnik LVADs and for the Sputnik PRBP, and finally (iv) to compare this between two generations of adult LVADs. This research is intended to expand the information on LV-LVAD interaction in order to optimize the choice of RBP speed rate control in the clinic regarding the degree of heart failure in adult and pediatric patients.In this work, energetic characteristics of (i) Sputnik 1 and (ii) Sputnik 2 connected to a hybrid adult mock circulation (HAMC)  and  to 66 mm. The maximum diameter was decreased from 34 mm  to 29 mm . The diaThe necessity to develop a device for pediatric patients imposed many obstacles. Therefore, the first phase of the Sputnik PRBP design involved the detailed elaboration of requirements for the pediatric patients, which significantly differed from the adult group . The twoThe working principle and design features of Sputnik PRBP are described in detail in the work of Dr. Telyshev et al . Herein,The main parts of the pump are made of titanium alloy, whereas the bearings used in the pump are made of CoMoCr alloy, as in the adult Sputnik LVADs. Moreover, the rotor of the Sputnik PRBP contains a permanent NdFeB magnet actuated by a brushless DC motor, the same as used in the first and second generations of the adult Sputnik LVADs.Thus, Sputnik PRBP is suitable for pediatric patients with body weight of 12–40 kg.For the study of the adult Sputnik LVADs, a mock circulation loop  based onPed(V),  Pes(V)) is modeled by chamber-specific time-varying elasticity functions e(t), that result in the function of pressure p for each chamber.Ees describes the chamber-specific elasticity and can be modified by the nondimensional contractility factor 0 < VCF ≤ 1 and Vu describes the volume when the transmural pressure is equal to zero and can be set individually for each chamber.In comparison to classical mock circulation loops, herein the heart and the cardiovascular system are exclusively modeled in the numerical domain and transferred into the physical domain as set points for the pump inlet and outlet. The cardiovascular system simulation is implemented as a simplified version of the model from  in the sThe hardware part of the mock circulation loop contains mainly two compartments made of polymethyl methacrylate and does not contain any valves, compliance chambers, or flow resistances. The chambers are actuated via voice coil actuators (VCAs) to reproduce fast pressure changes, whereas three gear pumps generate directed flow to keep the VCAs in the operating range. The adult mock circulation loop is capable to achieve an accuracy of ±1 mmHg and a settling time less than 20 ms. Invasive blood pressure sensors  are used to measure pressures in two compartments, whereas an ultrasonic flow probe is utilized to determine the pump flow . In addition, the hydrodynamic properties of blood are emulated with a glycol/water mixture .For the test under dynamic conditions with the Sputnik PRBP, a conventional pediatric mock circulation see  allowingThe system in The left pulsatile AV has a nominal volume of 72 ml corresponding to a dilated pediatric ventricle volume. It is a pump pneumatically driven by a membrane that simulates the heartbeat using the pneumatic control system. The pulsatile AV has an inlet and an outlet valve to prevent reverse flow of fluid into the hydraulic circuit. A 32% aqueous glycerol solution is used in the PSCL as the model fluid. This configuration of the mock circulation allows simulating normal pediatric systemic circulation and heart failure state. It should be clarified here that under the normal state, we mean summation of LV failure state with connected LVAD, and this applies to both flow and work. The left AV also has a second outlet providing the connection between the Sputnik PRBP inlet and the ventricle. The Sputnik PRBP outlet is connected to the aortic container. Before testing the Sputnik PRBP behavior and its influence on the system, the pump connection line was closed with a special flow restrictor.The pneumatic system including a pneumatic station and a pneumatic control unit is used to control the AV contraction through an electronic control system based on combined NI cDAQ-9174 and NI 9264 hardware implemented with the NI LabVIEW software . The contractility level of the pulsatile AV can be varied by altering the control signal amplitude and frequency. The Frank–Starling mechanism is reproduced by using EDP as a preload parameter in feedback.The data acquisition system consists of a pressure measurement system, a flow measurement system, and a data processing system based on combined NI cDAQ-9174 and NI 9205 hardware and NI LabVIEW software.Adult LVADs characteristics were analyzed in two operation modes of the HAMC. Each operation mode is characterized by nondimensional ventricle contractility factors (VCFs) of 0.5 and 0.25. These two operation modes correspond to mild and congestive heart failure states, respectively. An acute heart failure state in pediatric patient with the body mass of 15.2 kg [The energetic characteristics of Sputnik 1 and Sputnik 2 LVADs were obtained in a speed range of 5000–10000 rpm increasing in steps of 200 rpm. Sputnik PRBP operation was analyzed in the speed range of 6000–13000 rpm in steps of 200 rpm.PLV is the left ventricular pressure and VLV is the left ventricular volume.Poutis the LVAD outlet pressure, Pinis the LVAD inlet pressure, and QVADis the LVAD flow rate.The left ventricular stroke work, LVAD hydraulic work, and total work investigated from the energetic characteristics can be described as follows:ALV and AVAD.Left ventricular stroke work represents the area inside the closed contour formed by the left ventricular pressure-volume relationship. The LVAD hydraulic work, in its turn, is the time integral of the LVAD head pressure and flow rate product. Total work is the sum of the Also, the mean LVAD flow rate, the mean aortic valve flow rate, the end-diastolic volume, and the relationship between left ventricular stroke work and the LVAD hydraulic work were utilized to describe all simulated conditions. The characteristics were calculated for each cardiac cycle on a sample of obtained experiment data and were averaged over all cardiac cycles in each simulated condition.Qpumpmax, Qpumpmin, and Qpumpav are maximum, minimum, and average pump flow rates.Furthermore, pulsatility indices of pump flow rates were analyzed:Figures The work of the Sputnik 1 pump intersects with zero in the speed range of 6200–6400 rpm for a VCF of 0.5 and at 5400–5600 rpm for a VCF of 0.25 Figures . The totFigures Figures Sputnik 2 pump work intersects with zero in the speed ranges of 6400–6600 rpm and 5600–5800 rpm for VCFs of 0.5 and 0.25, respectively Figures . The totFigures We chose one of the Medos VAD ventricles the aortic valve leaflets of which are prolapsed as an overload on the aortic valve increase. Thus, aortic back flow is reached after a certain pump speed.Relations represented in The unloading tendency of the LV is observed in all simulations for all heart failure states with a connected LVAD, when the pump speed increases within a certain range. This, coupled with an increased average hydraulic pump work, leads to a systemic circulation performance improvement. This is also clearly indicated by the development of the average total work and the average total flow rate of the LV and the LVAD. The change from the partial support to full support is accompanied by the aortic valve closure followed by an aortic back flow. This behavior occurs at a certain operation mode for each LVAD and depends on the residual LV contractility. Thus, based on this operation mode, the LVAD becomes the only fluid actuator in the circulatory system.Figures 4In the case of the Sputnik PRBP, an average hydraulic pump work is negative in the speed range of 6000–7800 rpm, although the flow rates are positive. Also, there is an obvious correlation between the average aortic valve flow rate and the average hydraulic pump work, i.e., the hydraulic pump work exceeds the LV stroke work right after the aortic valve closure. This correlation does not match the adult Sputnik LVADs tendency, as the hydraulic pump work overshoots the LV stroke work before the aortic valve closes.The dependencies between the EDV and the stroke work for the Sputnik 1 and Sputnik 2 LVADs at a VCF of 0.25 have an inflection point, which corresponds to an aortic valve closure. At this point, the slope of the EDV becomes steeper as the stroke work decreases.Due to improvements in the design, the Sputnik 2 LVAD allows to achieve LV normal state characteristics slightly quicker than Sputnik 1 LVAD, i.e., at lower pump speed. An exception needs to be done for the LV and LVAD total work at a VCF of 0.25 which is achieved at the same speed as the Sputnik 1 LVAD. Almost simultaneously, the normal state work and the flow rate are achieved by the Sputnik 1 and Sputnik 2 LVADs, i.e., at similar pump speeds. In the case of the Sputnik PRBP, a normal level of the total work is achieved at a slightly lower speed in comparison to the normal flow rate. However, the speed difference is only 200 rpm. Thus, obtaining the normal average flow rate during a support with the Sputnik PRBP, it can be seen that the total work of a normal state along with sufficient LV unloading is achieved.EDV is another indicator of the LV unloading, since it decreases with increasing pump speed . The corAll pump flow rate pulsatility indices of the adult Sputnik LVADs for different VCFs converge to zero at high pump speeds (over 9000 rpm). This behavior is most likely brought by the fact that the LV, as the only pulsatile element of the entire system, ceases to pulse being unloaded with an increase in pump speed. Therefore, all characteristics including the pump flow rate become less pulsatile. The flow rate pulsatility index of the Sputnik PRBP shows the same but more gradual trend with respect to pump speed.The presented research shows that RBPs differently influence the LV depending on heart failure degree. Thus, significant support levels cannot be obtained for a VCF of 0.25 in the HAMC and for pediatric LV in the PMC without an aortic valve closure in comparison to a VCF of 0.5 in the HAMC. To solve this problem, the implementation of control algorithms providing a modulation of the LVAD speed in order to open the aortic valve and to unload the LV more efficiently is needed. Moreover, the importance of maintaining pulsatility has been suggested in many journals. There are restrictions for mechanical support when a patient's health is in a very poor condition. Algorithms of the physiological control may be exceptionally useful to overcome this issue. Ando et al. has recently created a pulsatile mode for continuous-flow left ventricular assist devices which can produce pulsatility comparable to the physiological pulsatile flow . BozkurtAn absence of the aortic back flow in the HAMC should be considered as a limitation of the presented study, since this condition is frequently observed in patients during LVAD support on relatively high speeds and its presence could lead to more accurate results for the adult Sputnik LVADs.The Frank–Starling mechanism is simulated according to equations for ventricular pressure and volume. It should be noted that there is no automated feedback mechanism simulating Frank–Starling mechanism in the pediatric mock circulatory system in this study. However, in our case, the Frank–Starling mechanism is implemented according to previously manually selected parameters of contractility and finite diastolic volume.The present work underlines the importance to simulate operating conditions of the human body during the development of a bioengineering device designed for implantation. The significance of pulsatility is highlighted in this work in addition to its importance in clinical applications . In this work, we investigated the interaction between different Sputnik LVADs and the LV with different degrees of HF. We evaluated various LVADs: adult Sputnik 1, Sputnik 2, and Sputnik pediatric RBP (PRBP) engineered for pediatric patients with body a weight between 12 kg and 40 kg. We show the influence of the Sputnik LVADs on the LV depending on the HF degree by the estimation crucial parameters of LV unloading and investigation energetic characteristics of the LV-LVAD interaction for adult and pediatric Sputnik LVADs. Finally, we state that since significant support levels cannot be obtained for a VCF of 0.25 in the HAMC and for pediatric LV in the PMC without the aortic valve closure in comparison to a VCF of 0.5 in the HAMC, it is necessary to investigate control algorithms providing a modulation of the LVAD speed in order to open the aortic valve and unload the LV more efficiently.


Myocardial strain is a well validated parameter for estimating left ventricular (LV) performance. The aim of our study was to evaluate the inter-study as well as intra- and interobserver reproducibility of fast-SENC derived myocardial strain. Eighteen subjects  underwent a cardiac MRI examination including fast-SENC acquisition for evaluating left ventricular global longitudinal (GLS) and circumferential strain (GCS) as well as left ventricular ejection fraction (LVEF). The examination was repeated after 63 [range 49‒87] days and analyzed by two experienced observers. Ten datasets were repeatedly assessed after 1 month by the same observer to test intraobserver variability. The reproducibility was measured using the intraclass correlation coefficient (ICC) and Bland-Altman analysis. Patients with heart failure demonstrated reduced GLS and GCS compared to healthy controls . The test-retest analysis showed excellent ICC for LVEF (0.92), GLS (0.94) and GCS (0.95). GLS exhibited excellent ICC (0.99) in both intra- and interobserver variability analysis with very narrow limits of agreement (−0.6 to 0.5 for intraobserver and −1.3 to 0.96 for interobserver agreement). Similarly, GCS showed excellent ICC (0.99) in both variability analyses with narrow limits of agreement (−1.1 to 1.2 for intraobserver and −1.7 to 1.3 for interobserver agreement), whereas LVEF showed larger limits of agreement (−14.4 to 10.1). The analysis of fast-SENC derived myocardial strain using cardiac MRI provides a highly reproducible method for assessing LV functional performance. However, several studies have pointed out the dependence of this parameter on the loading conditions of the heart at the time of the measurement2. In addition, in a variety of cardiovascular diseases, LVEF is not able to detect subtle changes in myocardial performance, usually seen in the early phases of the disease3. Thus, parameters of myocardial deformation such as myocardial strain were developed with the purpose of better characterization of myocardial regional function. Numerous studies have shown the utility of myocardial strain in the diagnosis of several pathologies, identifying subclinical myocardial changes as well as providing strong prognostic value for future cardiac events5.Quantitative assessment of left ventricular (LV) functional performance remains one of the cornerstones in the diagnosis and treatment of cardiovascular patients. LV ejection fraction (LVEF) is the most used clinical parameter in evaluating left ventricular performance. Many clinical decisions in patients with cardiovascular conditions are based on the absolute value of LVEF7. Numerous studies showed the incremental value of echocardiographic strain in identifying subclinical dysfunction in cancer patients and establishing prognosis in patients with ischemic heart disease8. However, dependency on image quality, high inter- and intraobserver reproducibility as well as inter-vendor variability hampered the widespread use of this technique in the clinical routine. Cardiac magnetic resonance (CMR) imaging, on the other hand, offers an integrative approach in the evaluation of the LV, providing information regarding morphology, function, hemodynamics and tissue characterization, all in one examination and without exposing the patient to ionizing radiation. Additionally, regional myocardial function can be measured using CMR. One of the first techniques employed in extracting myocardial strain was myocardial tagging9. The method was shown to have a good reproducibility, with low coefficient of variations for interobserver and intraobserver analysis10. Although it proved useful in identifying viable myocardium and evaluating diastolic function, the method is still hampered by low spatial resolution, long acquisition times and even longer post-processing times11. Phase velocity mapping (PVM), another method employed in the early days of CMR for extracting myocardial deformation parameters, uses the same principles that apply for extracting flow velocities. However, the need for measuring relatively low myocardial velocities compared to blood flow velocities results in longer acquisition times and phase distortion12. Displacement encoded with simulated echoes (DENSE) is a more recent method developed for measuring myocardial mechanics13. In vitro studies showed a very good accuracy in measuring deformation14. Furthermore, the method provided reproducible results in animal and human studies16. Although the technique involves fast post-processing, the technical aspects needed for measuring displacement may result in a low signal to noise ratio12. In contrast, fast strain encoded CMR imaging (fast-SENC) provides real-time acquisition of myocardial strain in a single heart beat17. The method is well validated in vitro and was shown to be clinically relevant in identifying myocardial ischemia in low dose dobutamine stress examinations18.Several non-invasive methods can be employed for extracting myocardial strain. Echocardiography, using either tissue Doppler imaging or speckle tracking, provides a readily available technique for measuring myocardial strainThe aim of our study was to evaluate the reproducibility at interstudy, interobserver and intraobserver levels for measuring longitudinal and circumferential strain using fast-SENC technique in a population of healthy volunteers and patients with heart failure (HF).Eighteen individuals  underwent a CMR scan including fast-SENC acquisitions. The study was approved by the Ethics Committee of the Charité-University Medicine Berlin and complied with the Declaration of Helsinki. All individuals gave written informed consent before participating in the study.The acquisition was performed on a 1.5 Tesla MRI scanner  using a five-element phased array cardiac coil for signal reception. Data acquisition was triggered on the R-wave using a 4-lead vector ECG.17 SENC method based on the acquisition of two images with different frequency modulation was employed. Bright regions in the two frequency modulation images represent static and contracting tissues, respectively. Circumferential and longitudinal strains in a range from 5% to −30% were encoded, where negative values represent positive contraction. A real time SENC variant with single-shot spiral readouts was employed. Typical SENC imaging parameters were as follows: field-of-view = 256 × 256 mm², slice thickness 10 mm, voxel size 4 × 4 × 10 mm³, reconstructed resolution at 1 × 1 × 10 mm3 using zero-filled interpolation (in-plane ZIP 1024), single-shot spiral readout (3 interleaves) with acquisition time TA = 10 ms, flip angle = 30°, effective echo time (TE) = 0.7 ms, repetition time (TR) = 12 ms, temporal resolution = 36 ms, typical number of acquired heart phases = 22, spectrally selective fat suppression (SPIR), total acquisition time per slice <1 s. Data were acquired in three long-axis  views, and three short-axis views at different LV levels .A previously describedAll fast-SENC images were uploaded from the scanner into dedicated MyoStrain software . All images were analyzed by one observer (SG). Before starting the analysis, the observer was trained by a representative of the software company with an emphasis on possible sources of error. The LV circumferential strain was extracted from three long-axis views, whereas longitudinal strain was extracted from three short-axis images . The endocardial and epicardial borders were drawn at the end-systolic cardiac phase and after application of the automatic tissue tracking algorithm software, the borders were traced throughout the entire cardiac cycle. The tracking was verified and manually corrected when needed for each segment. In addition, LVEF was calculated from all three long-axis images. A 16-segment model was used for the longitudinal strain and an 18-segment model for the circumferential strain. Global longitudinal strain (GLS) was expressed as the average value of all 16 segments obtained from the short-axis views. Similarly, global circumferential strain (GCS) was the average value of the 18 segments obtained in the long-axis views. As myocardial shortening occurs in both longitudinal and circumferential directions in systole, the strain values are consequently negative and are so reported. However, throughout the text, and in keeping with most of the literature on the subject, we will refer to the absolute values .All 18 individuals underwent a second identical CMR examination at a median of 63 [range 49‒87] days after the first examination. To avoid recollection bias of the involved CMR staff, a minimum of 6 weeks difference have been between the first and second scan. Care was taken that acquisitions were performed at the same levels of the heart Figs  and thatTo test for intraobserver variability, ten random datasets were reanalyzed 1 month after the first analysis by the first observer (SG), blinded to the results of the first analysis. For interobserver variability these 10 datasets were analyzed by a second observer (VZ) who was blinded to the results of the first observer.19. In addition, for the test-retest variability, the coefficient of variation was calculated. Receiver operator analysis (ROC) analysis was used to determine the optimal value for GLS and GCS, respectively, to identify a reduced LVEF (LVEF <50%). A p value <0.05 was considered statistically significant. All data was analyzed using MedCalc Statistical Software .Data are expressed as mean ± standard deviation. A t-test was used to compare continuous variables. Test-retest, interobserver and intraobserver variability were tested using intraclass correlation coefficient (ICC) and Bland-Altman analysis. The following levels of agreement were used: excellent for ICC >0.74, good for ICC 0.6‒0.74, fair for ICC 0.4‒0.59, poor for ICC <0.4Table We found excellent intersession reproducibility of measurements of GLS and GCS as shown by the respective ICC (0.93 and 0.95 for GLS and GCS respectively). In addition, the Bland-Altman analysis showed narrow limits of agreement for these two parameters Table . SimilarIn both inter and intraobserver analysis, the reproducibility of strain measurements and LVEF was excellent Tables  and 4. MA value of −18.6% for GLS identified a LVEF <50% with sensitivity of 83.3% and specificity of 83.3%. Similarly, a GCS value of −17.1% identified a LVEF <50% with 100% sensitivity and 83.3% specificity  excellent interstudy as well as interobserver and intraobserver agreement for these functional LV parameters. (ii) Fast-SENC derived GLS and GCS allows very good discrimination between patients with normal LV performance and those with reduced LVEF.in vitro studies, the widespread use of this method is still hampered by long acquisition and post-processing times21. SENC was first proposed in 2001 as a method to extract longitudinal strain from short-axis images using harmonic phase MRI22. For the strain values to be extracted, out of plane phase-encoding gradients orthogonal to the image plane are employed. Thus, short-axis images  are used to generate longitudinal strain and long-axis images  to obtain circumferential strain. At first, the method was difficult to implement because of long breath-hold periods necessary for the acquisition of multiple heart beats. The method improved, ultimately allowing image acquisition in a single heartbeat – fast-SENC17. The fast-SENC method was validated in vitro as well as in normal human subjects. Strain values derived using fast-SENC protocols correlated closely to values derived from CMR-tagging23. In addition, the method proved superior to visual wall motion analysis during dobutamine stress CMR and allowed the diagnosis of coronary artery disease at lower stages of stress24. Another advantage of the method is its ability to provide information related to diastolic function of the LV25. Thus, it enabled better assessment of the diastolic dysfunction of patients with diabetes mellitus. The method was shown to be useful in the analysis of the right ventricle, offering better characterization of right ventricular performance in healthy individuals and patients with pulmonary hypertension26.Several CMR techniques can be employed for extracting myocardial deformation parameters. Historically, myocardial tagging was the first technique used to measure myocardial strain and it later became the standard to which other techniques were compared. Although myocardial tagging is well validated through several In our study, we analyzed strain values on a wide range of LVEF. We found that both GLS and GCS have very good discriminatory power in differentiating between normal and reduced LVEF.et al. compared strain values extracted with echocardiography and CMR, and found a very large variation between the two methods as well as a significant bias in the echocardiographic derived strain measurements27. Consequently, in the light of their findings, the authors questioned the clinical usefulness of echo-derived strain measurements. In addition, strain measurements obtained with echocardiography are vendor dependent, as shown by a recent study by Mirea et al.28. The authors found high variability between different vendors in strain values. The ICC between different vendors was as low as 0.52. In addition, as much as 22% of segments had to be excluded from the analysis due to low image quality. SENC acquisition, on the other hand, is vendor independent and can be implemented in the MRI machines of different vendors.An abundance of data exists confirming the role of myocardial strain, derived using either echocardiography or CMR, in the diagnosis, treatment and prognosis of various cardiovascular conditions. However, a lack of standardization still hampers the implementation of parameters of myocardial deformation imaging in clinical practice. This is mainly due to still unsatisfactory high variability in measurements. High inter- and intraobserver and test-retest variability reduces the consistency of the method. This in turn makes reliable detection of small changes in regional myocardial function difficult to achieve. A recent study by Amzulescu 29. Two more recent studies confirmed the good reproducibility of myocardial strain derived with tagging techniques30. However, in the study by Donekel et al., the ICC for interstudy reproducibility was lower for the same parameters30. A validation study by Kar et al. showed very narrow limits of agreement between repeated measurements for circumferential strain extracted with DENSE16. A study by Miyagi et al. performed in 24 patients with suspected coronary artery disease noted an excellent interobserver agreement with an ICC >0.95 for estimating myocardial strain31. Similar results were found in a more recent study performed in 17 healthy volunteers32. Similar to myocardial tagging, however, the agreement was moderate when testing for interstudy variability.The data from studies performed on CMR derived myocardial strain show better reproducibility compared to echocardiography. An initial study performed on 24 participants showed very good agreement in the measurement of circumferential strain using myocardial tagging34. In addition, the two studies with the highest number of healthy controls do not have overlapping values for longitudinal and circumferential strain36. As seen with echocardiography, different software from different vendors produces inconsistent results as shown by Schuster et al.37. Lastly, the limits of agreement when testing the reproducibility of strain measurements using FT are less narrow compared to those in our study38.In recent years, feature tracking (FT) has been used for deriving deformation parameters from conventional cine CMR acquisitions. The method tracks individual “features” of a predetermined region of interest throughout the entire cardiac cycle. The main advantage of the method is that no additional acquisition is necessary during the CMR scan. When compared to CMR-tagging, the consistency of FT was not uniform between studiesTo the best of our knowledge, this the first study to test the reproducibility (including interstudy variability) of strain measurements derived with fast-SENC. In comparison to other methods, we showed excellent ICC with very narrow limits of agreement for both longitudinal and circumferential strain. Thus, fast-SENC derived strain measurements are suitable for serial studies and could reliably detect subclinical changes in myocardial function.The main limitation of our study is related to small population size. However, this is in concordance with most of the reproducibility studies to date. In addition, our sample size included both healthy individuals and patients with reduced LVEF.The analysis of fast-SENC derived myocardial strain using cardiac MRI provides a highly reproducible method for assessing left ventricular performance.


Myocardial infarction and post-infarction left ventricular remodelling involve a high risk of morbidity and mortality. For this reason, ongoing research is being conducted in order to learn the mechanisms of unfavourable left ventricular remodelling following a myocardial infarction. New biomarkers are also being sought that would allow for early identification of patients with a high risk of post-infarction remodelling and dysfunction of the left ventricle. In recent years, there has been ever more experimental data that confirms the significance of microRNA in cardiovascular diseases. It has been confirmed that microRNAs are stable in systemic circulation, and can be directly measured in patients’ blood. It has been found that significant changes occur in the concentrations of various types of microRNA in myocardial infarction and heart failure patients. Various types of microRNA are also currently being intensively researched in terms of their usefulness as markers of cardiomyocyte necrosis, and predictors of the post-infarction heart failure development. This paper is a summary of the current knowledge on the significance of microRNA in post-infarction left ventricular remodelling and heart failure. Despite significant progress in the treatment of cardiovascular diseases, they continue to be the principal cause of death in developed countries. This is mainly due to acute coronary syndromes. The current methods used in the treatment of myocardial infarction patients have significantly lowered early mortality from this disease. However, many myocardial infarction patients suffer from unfavourable left ventricular remodelling and the development of heart failure. Although there have been improvements in its treatment, heart failure remains a very serious clinical problem. It causes high mortality, and many patients suffer from severe symptoms despite optimal treatment. For this reason, efforts are being made both to understand the mechanisms that determine unfavourable left ventricular remodelling and the development of heart failure in some myocardial infarction patients, and to learn about the protective mechanisms that safeguard other patients from such remodelling.Many different studies have confirmed the instance of significant changes in the concentrations of cytokines and soluble tumour necrosis factor (TNF) family receptors in the plasma of patients in the acute phase of myocardial infarction –6. TheseThe presence of a smaller number of MSC in the peripheral blood in the acute phase of myocardial infarction has been demonstrated in patients who go on to develop unfavourable left ventricular remodelling and heart failure when compared with those patients in whom this does not occur . These oThis is a group of small, non-coding RNA molecules which regulate the expression of genes at the transcriptional and post-transcriptional stages. MiRNAs are the most numerous group of small regulatory RNAs, known as srRNAs. SrRNAs include miRNAs, which take part in gene silencing at the post-transcriptional or transcriptional stage, small interfering RNAs (siRNAs), which silence genes at the post-transcriptional stage, and trans-acting siRNAs, anti-sense iRNAs and pivi-interactive RNAs . MicroRNGenes for miRNAs occur in different locations. They can occur in introns and exons of structural genes and in intergenic regions. At the initial formation of an miRNA, the so-called pri-miRNA, is formed with the participation of polymerase II , 11, 13.The growing interest in miRNAs occurring in humans is due to the role that the molecules play in many important physiological and pathological processes. It has been shown that miRNAs in people take part in the regulation of such processes as the differentiation of haematopoietic stem cells, the differentiation of skeletal muscle cells, neurogenesis, embryogenesis, angiogenesis, insulin secretion, differentiation of mononuclear cells, and the formation and activity of immune system cells –30. TheiParticularly close attention has been paid recently to some miRNAs due to their participation in the regulation of the function of vascular endothelium and the endothelial cells found in the heart, in addition to their effect on left ventricular remodelling after a myocardial infarction. More and more research is finding proof of the key role miRNAs play in myocardial infarction and in the occurrence of post-infarction left ventricular remodelling. This has been demonstrated by miR–532 among others . ResearcThe importance of other types of miRNA in myocardial infarction and post-infarction left ventricular remodelling has also been confirmed. One of these is miR–145. It has been shown that the plasma concentrations of miR–145 were significantly lower in patients who had suffered an acute myocardial infarction than in people without coronary disease. Additionally, in a group of myocardial infarction patients, a lower plasma concentration of this particular miRNA was related to significantly higher concentrations of B-type natriuretic peptide and troponin T, and a significantly lower left ventricular ejection fraction . It was It was shown that miR–155 is also related to unfavourable post-infarction left ventricular remodelling . It has MiR–124 is meanwhile recognised as a cardiomyocyte necrosis marker in acute myocardial infarction. This was confirmed in research performed on patients with acute myocardial infarction and in less than 6 h from the onset of their symptoms . PeripheIn another prospective study on a group of 150 patients with acute myocardial infarction, the prognostic value of group 4 miRNA plasma concentrations was assessed, which were found to influence the expression of genes related to left ventricular remodelling . A panelNewer research has shown the participation of miR–150 in angiogenesis and ischaemia-induced neovascularisation . These pGrowing interest in miRNAs as biomarkers useful in cardiovascular diseases, is due to their participation in pathophysiological processes related to cardiovascular diseases as well as their stability in blood and in urine . IncreasThe diagnostic and prognostic significance of miR–1 for post-infarction left ventricular remodelling has also been confirmed in the SITAGRAMI clinical trial patient population . Plasma The pathophysiological mechanisms relating to the effect of the remaining microRNAs mentioned above are still being researched. One such study confirmed that an increase in the expression of miR–133a in mice with pressure overload of the left ventricle caused by transverse aortic constriction, reduced myocardial fibrosis by inhibiting the expression of connective tissue growth factor (CTGF) . This reIt was also shown that there was a significant increase in the expression of miR–184 in the acute phase of a myocardial infarction, with a peak blood concentration reached 24 h after the beginning of myocardial infarction symptoms . This waThe crucial importance of miRNAs in the process of cardiomyocyte apoptosis and myocardial fibrosis under hypoxic conditions in myocardial infarction has also been confirmed in research by Yi Sun Song et al. . These rThe effect of miRNAs on the intensification of post-infarction myocardial fibrosis processes was also studied in terms of their effect on expression of TGF–beta1, which is a known mediator of organ fibrosis processes and regulates the function of fibroblasts . It was In cell culture conditions, human cardiac fibroblasts (HCFs) were tested by transfecting them, among others, with miR–125b using plasmid vectors . HCFs seOther research confirmed the influence of miR–17 on increased ECM degradation in the heart during a myocardial infarction. It was shown that the substantial rise in miR–17 expression during a myocardial infarction was connected to significant suppression in the expression of tissue inhibitor of metalloproteinase 1 and 2 (TIMP1/2), which resulted in increased proteolytic matrix metalloproteinase 9 (MMP9) activity and caused an increase in ECM degradation as well as increased post-infarction left ventricular dysfunction . In addiIn the authors’ opinion, one early clinical application for the determination of microRNA plasma concentrations may possibly be their use as markers of cardiomyocyte necrosis and as predictors of post-infarction left ventricular remodelling and the development of heart failure. For example, it has been confirmed in clinical trials that miR–24 is a specific marker of cardiomyocyte necrosis, correlating well with classical markers such as troponin I or CK-MB. It was also confirmed that the level of miR–24 myocardial infarction peaks even earlier than that of troponin I . In addiHowever, the most attractive, though more long-term, perspective seems to be in using our knowledge of microRNA in the treatment of patients with cardiovascular diseases. One example is an interesting therapeutic concept based on the experimental data collected so far on the role of miR–125b in stimulating the proliferation and migration of HCF and increasing the expression of alpha–SMA and collagen I and III by reducing the expression of SRP5. The concept is based on the transfection of HCF by SFRPS using plasmid vectors . As the Another potential, future application of this data about miRNA is to treat patients, in clinical practice, with the use of BM-MSCs. Experiments on myocardial infarction in animals have confirmed a reduction in the intensity of apoptosis of cardiomyocytes and of myocardial fibrosis following myocardial infarction, as a result of therapy using various types of MSCs. It has been confirmed that this is mainly due to the paracrine effect of factors released from MSCs, which have been transplanted in the area of myocardial damage, and not by direct regeneration of the myocardium from BM-MSC. The basic substance of this paracrine activity, released by MSCs, is VEGF, which strongly inhibits the expression of miR–23a and miR–92a, which, in turn, promote apoptosis of cardiomyocytes and myocardial fibrosis. The experimental data, which has been collected, confirms that the reduction in miR–23a and miR–92a expression by VEGF plays a key role in the beneficial therapeutic effect of BM–MSC transplantation in a model of myocardial infarction in animals. This forms the basis for future developments in therapies for patients with myocardial infarction, which could use paracrine factors such as VEGF to suppress the expression of miR–23a and miR–92a, and thus inhibit apoptosis of cardiomyocytes and myocardial fibrosis.The main problem with the miRNA-based therapies is that a single miRNA controls expression of many genes and changing the expression of a miRNA can cause many different side effects. In terms of solving this problem some new technics have been developed but future studies are still needed. Advanced technologies are also required to effectively deliver specific miRNAs to the designated organs or tissues. So there remains many real challenges to overcome in this field, but physicians should be aware of the potential of introducing miRNA-based therapies into clinical medicine in the future.Due to the growing body of data confirming the crucial role of different miRNAs in post-infarction heart remodelling and heart failure, miRNAs can be seen not only as potential diagnostic or prognostic markers, but also as potential therapeutic targets for this group of diseases. The relationships shown so far between different types of miRNA and cardiomyocyte apoptosis processes and myocardium fibrosis open the way for the search for detailed pathogenic mechanisms that are the basis of these relationships. Following on from this, is the search for potential therapies in the field of those cardiovascular diseases, for which there is currently a severe lack of effective treatment.


Congenital heart disease is the most common congenital malformation occurring in just over 1% of live births. With the advances in noninvasive diagnostics, interventional catheterization, congenital heart surgery, cardiopulmonary bypass and postoperative care a dramatic change in the prognosis for children born with congenital heart disease has been observed the last decades . Today mPatients with congenital cardiac malformations can be divided into those who do not need surgery , because their condition will either be of none or very small significance  or because it will heal with time . Those who have undergone an intervention by catheter and/or surgery and who which can either be considered “cured”, such as patients with persistent ductus arteriosus, VSD and small ASD treated with surgery or catheter. These patients are in general not followed up after childhood and will most likely have no late consequences of their condition. However, a large portion of patients, operated on in childhood may be considered as palliated. They will thus be subject to further medical, surgical and catheter-based interventions. Almost six out of 1000 adults will have a congenital condition that merits life-long follow-up .The risk for the elderly patients with a palliated or un-operated congenital heart condition to develop atrial fibrillation is very high . The samAs for many persons and patients with other conditions, lifestyle has an important impact on the cardiovascular health also for patients with congenital heart disease. In general, the degree of physical activity tends to be lower for adult with congenital heart disease, possibly because of hesitation from patients themselves, from parents and teachers during childhood restricting physical activity. Many patients with congenital heart conditions are performing less well on a treadmill and this is to a significant extent, caused by lack of training, lack of muscular strength .The dramatic improvements in medical care for patients with congenital heart conditions have resulted in a dramatic increase in survival. At the same time the physicians caring for elderly patients will see increasing numbers of patients with congenital heart disease who survive until old age. They will bring with them an increased risk of cardiovascular morbidity, such as atrial fibrillations, stroke, intracerebral hemorrhage, acute myocardial infarction and heart failure. On top of these inherited risks, patients with adult congenital heart disease will also be subject to the negative effects of an unhealthy lifestyle. Regardless of age these patients should be considered, and are at a higher than average risk for mortality and morbidity. While we do not yet specifically know when or where and when we should start preventive medical treatment such as anticoagulation or cholesterol-lowering treatment, meticulous care to medical treatment and to lifestyle factors is warranted, as illustrated in