Heart failure (HF) can be defined as cardiac structural or functional abnormality leading to a series of symptoms due to deficiency of oxygen delivery. In the clinical practice, acute heart failure (AHF) is usually performed as cardiogenic shock (CS), pulmonary edema, and single or double ventricle congestive heart failure. CS refers to depressed or insufficient cardiac output (CO) attributable to myocardial infarction, fulminant myocarditis, acute circulatory failure attributable to intractable arrhythmias or the exacerbation of chronic heart failure, postcardiotomy low CO syndrome, and so forth. Epidemiological studies have shown that CS has higher in-hospital mortality in patients with AHF. Besides, we call the induced, sustained circulatory failure even after administration of high doses of inotropes and vasopressors refractory cardiogenic shock. In handling these cases, mechanical circulatory support devices are usually needed. In this review, we discuss the current application status and clinical points in utilizing extracorporeal membrane oxygenation (ECMO). Extracorporeal membrane oxygenation (ECMO) evolved from cardiopulmonary bypass (CPB) and provides prolonged hemodynamic and respiratory support outside of the operating suite . With thThe basic ECMO circuit includes a flow pump, an external membrane oxygenator, vascular cannulas, connecting tubes, a heat exchanger, and monitoring devices  Figure . The cirIn this review, we focus on the current application status and clinical points of VA ECMO in CS.ECMO is a high-tech medical treatment option that requires a multidisciplinary team with specialists from cardiothoracic surgery, cardiology, perfusion, intensive care medicine, anesthesiology, respiratory care, and nursing care , 8. The Etiological studies have shown that CS is mainly caused by myocardial infarction, fulminant myocarditis, the acute exacerbation of chronic heart failure (CHF), acute circulatory failure attributable to intractable arrhythmias, postcardiotomy low CO syndrome, and acute heart failure attributable to drug intoxication, and so forth –12. ResuCardiogenic shock:Acute MI.Fulminant myocarditis.Acute exacerbation of CHF.Acute circulatory failure attributable to intractable arrhythmias.Postcardiotomy low CO syndrome.Acute heart failure attributable to drug intoxication.Possible concomitant respiratory failure :2 : FiO2 is ≤100 mmHg on ventilators setting that includes positive end-expiratory pressure ≥5 cmH2O, with supportive clinical features including compliance <0.5 mL/cmH2O/kg).Severe ARDS (defined as PaO2 : FiO2 ratio < 100).Severe, refractory hypoxia .Significant or symptomatic pulmonary hypertension.Pulmonary shunt fraction >30%.Cardiac arrest requiring eCPR. Common indications for venoarterial extracorporeal membrane oxygenation (VA ECMO) are as follows:In general, ECMO may be regarded as a bridge to anticipated recovery, to heart or lung transplant, or to long-term ventricular assist device (VAD). Hence, the most common contraindication is nonrecoverable cardiac failure without indication for transplant or long-term VAD. ECMO should not be instituted to increase the course and costs of the illness without any subsistent possibility of survival or acceptable quality of life . ECMO maOther specific contraindications include continuously progressive systemic disease , etc.) , coagulaAbsolute contraindications:Nonrecoverable cardiac failure without indication for transplantation or long-term VAD.Severe, irreversible brain damage without realistic possibility of reviving.Severe aortic regurgitation.Relative contraindications:Continuously progressive systemic diseases.Coagulation disorder.Existent multiorgan failure.Dissatisfied correction of cardiac deformity.Mechanical ventilation >10 days.Aortic dissection. Common contraindications to venoarterial extracorporeal membrane oxygenation (VA ECMO) are as follows:The circuit should be proper flushed with multiple electrolyte solution or normal saline priming. Cannulation for VA ECMO can be central or peripheral. In central cannulation, a venous cannula is inserted in the right atrium and an arterial cannula is implanted in the ascending aorta. This mode is mainly chosen in compelled implantation with open-heart surgery. In peripheral cannulation, venous cannula from femoral vein to the inferior vena cava and femoral arterial cannulation (IVC-FA) are mostly adopted for VA ECMO in adults . Besides2) >90% ; venous oxyhemoglobin saturation (SvO2) >65% (measured in venous drainage tube); hematocrit of 30–40% or with hemoglobin (Hb) >10 mg/dL or more; blood platelet count >10 000/mm3 [2) in the arterial line and partial pressure of oxygen (PaO2) of 100–150 mmHg in patient's right radial artery. Increased gas flow can realize CO2 clearance and reduce arterial partial pressure of CO2 (PaCO2) which is usually controlled between 35 and 45 mmHg. Mild hypothermia may be recommended if brain damage is suspected. Fever and chill should be treated to decrease oxygen consumption [2) can be calculated according to the following formula:2 is oxygen consumption (mL/min), SaO2 is arterial oxyhemoglobin saturation (%), SvO2 is venous oxyhemoglobin saturation (%), Hb is hemoglobin (mg/dL), and F is blood flow rate (L/min).Available management of ECMO needs in-depth knowledge and controls of clinical targets related to extracorporeal circulation. After anticoagulation with unfractionated heparin for an activated clotting time (ACT) of 180–210 seconds or an activated partial thromboplastin time (APTT) of >1.5 times the normal, the ECMO assist can be undertaken. Initial settings are shown as follows: perfusion flow of 50–80 mL/kg·min in adults (80–150 mL/kg·min in children and infants); arterial oxyhemoglobin saturation  mostly develops in the arterial cannula and oxygenator . When viIt is well known that CS could manifest as depressed or insufficient cardiac output, presenting a reduced cardiac index and low blood pressure which induces poor myocardial perfusion and profound depression of myocardial contractility . The red2O to keep alveolar recruitment, limiting tidal volumes (VT) to 4–6 cc/kg, breathing rate to 4–8 times/min, FiO2 to no more than 50%, and airway plateau pressure to ≤30 cmH2O. If the SvO2 is below the target, blood flow rate can be increased. Expansion of intravascular volume and increasing of hemoglobin concentration may also be undertaken to ensure adequate tissue perfusion. Majority of CO2 removal can be accomplished by an increasing of gas flow to oxygenator, instead of ventilator setting. Changes in flow rate on hemodynamics should be closely supervised with monitoring of ventilator settings.Protective lung ventilation strategies should be undertaken to minimize ventilator-induced lung injury, such as barotrauma and volutrauma, and accelerate respiratory recovery as possible. These include using positive end-expiratory pressure (PEEP) of usually 6–10 cmHDecompression of the right and left ventricle should be achieved in patients with VA ECMO because myocardial injury may occur if atrium and ventricle become distended. Frequent echocardiograms are recommended to evaluate cardiac function. Depression of the right ventricle can be realized by increasing drainage flow and adjusting the position of venous cannula. Adequate venous drainage is the key point to prevent excessive preload. Still, a small amount of blood may pass through pulmonary circulation, causing left heart overexpansion when lacking enough contractility to open the aortic valve. In this situation, addition of a vent cannula or percutaneous VAD, such as Impella, should be considered to decompress the ventricle .2 and a significant difference was found between the IVC and the SVC, explaining how differential hypoxia is attenuated by alternative modes of cannulation [Differential hypoxia has been reported which could cause insufficient oxygen supply to vital organs, such as the brain and heart, in respiratory dysfunction patients with femoral VA ECMO  . If the nulation .Neurological morbidity has become a significant concern as a more important role played by VA ECMO in treating acute heart failure for many patients. Brain death occurred in 7% to 21% of the cases of ECMO treated adults in some ECMO centers . Additio3) were risk factors associated with mortality, whereas younger age, lower weight, acute myocarditis, heart transplant, refractory ventricular tachycardia or fibrillation, higher diastolic blood pressure, and lower peak inspiratory pressure were protective [Lactate has been proposed as a marker of tissue perfusion that is influenced by not only macrocirculation but also microcirculation, whereas traditional hemodynamic parameters have been suggested to be unreliable . Lactateotective .Several open questions remain in VA ECMO therapy such as insertion timing and appropriate patient selection. An early use of VA ECMO in CS patients could warrant the body perfusion and prevent the development of MODS. However, complications associated with invasive mechanical support devices might lead to adverse clinical outcome in patients who still had noninvasive therapeutic options. The balance between circulatory support efficacy and its device-related complications should be considered. Furthermore, there are still no widely approved, evidential, accurate criteria of initiating VA ECMO that the current decision is more subjective. Despite these uncertainties, considering the use of a percutaneous assist device for circulatory support in refractory CS is recommended by European and American guidelines.ECMO is a high-tech medical treatment option that requires a multidisciplinary team. The decision to institute ECMO should be based on prior experience of ECMO team and hospital resources. VA ECMO plays a potential role in treating refractory cardiogenic shock, especially in patients with severe cardiogenic shock and combined respiratory failure. VA ECMO should be regarded as a bridge to anticipated recovery, to heart or lung transplant, or to long-term VAD. From the early days of VA ECMO support for refractory cardiogenic shock, the modality had been proved effective to prevent or reverse MODS, to improve hemodynamics and outcome in CS.


Here we provide a novel index utilizing LV normalized torsion shear angle Torsion shear angle Sixty resistant hypertension patients (HTN), forty control volunteers were studied using cardiovascular magnetic resonance with tissue tagging. Volumetric and torsional parameters were evaluated.HTN demonstrated concentric remodeling with preserved ejection fraction. HTN had significantly decreased normalized early filling rate, early diastolic mitral annulus velocity and E/A  vs. control. Torsion hysteresis area was greater  and peak Torsion hysteresis area and peak early diastolic  Left ventricular (LV) diastolic dysfunction is characterized by abnormal myocardial mechanical properties that include impaired diastolic distensibility, impaired LV filling and slow or delayed myocardial relaxation . Up to 5Invasive hemodynamic measurements, such as the time constant of relaxation(1), τ, and LV end diastolic pressure volume relationship (EDPVR)  are consLV twist, measured as the myocardial rotation gradient from the base to apex along a longitudinal axis , is an iφ is indicated as V is indicated as In this paper, a global approach utilizing normalized LV torsion shear angle volume . Detailed methodology for enrollment of HTN patients in this prospective study design was previously described . The norCine CMR was performed on a 1.5-T MRI scanner  optimized for cardiac application. Electrocardiographically gated breath-hold steady-state free precision technique was used to obtain standard  views using the following general parameters: slice thickness of the imaging planes 8 mm, field of view 40 × 40 cm, scan matrix 256 × 128, flip angle 45°, repetition/echo times 3.8/1.6 ms, views per segment 8–10, number of reconstructed cardiac phases 20.1 relaxation, tagged image derived parameters were only valid throughout systole and the first 67% of diastole.Tagged CMR was done on exact slice prescriptions as above by applying grid tagging to the short axis views and stripe tagging to long axis views using spatial modulation of magnetization encoding gradients method (FGR-SPAMM) as previously described  with folLV geometric parameters were measured from endocardial and epicardial contours manually traced on cine images acquired near end-diastole (ED) and end-systole (ES). These contours were propagated throughout the cardiac cycle using in-house software . LV voluφ at timeframe t was computed as [Two-dimensional (2D) strain at each timeframe and rates were measured using harmonic phase (HARP) analysis . 2D basaputed as \documentρ(t) is the epicardial radius at time t and L is the distance between the basal and distal slices at ED timeframe. 2D φt curve was therefore constructed for each subject.where φt curve was normalized by its maximum to generate Vt curve was normalized by its maximum V to generate t curve and t curve were interpolated with 10 and 18 time points respectively to create the For each subject, the mentclass2pt{minimmentclass2pt{minimt test (for continuous variables) and Fisher’s exact test  were conducted to compare control and HTN in terms of demographic, geometric, and functional variables. Pearson’s correlation analysis was THA and other CMR-derived indices of LV diastolic function  as well as LV mass/volume ratio and mean atrial pressure (MAP). We also created multivariate model for torsional and strain rate parameters to adjust for age using linear regression models.Student’s two-sample Data are in mean ± standard deviation (SD). A P < 0.05 was considered statistically significant. All statistical analysis was performed using SAS version 9.3.Control’s mean age was significantly lower than that of HTN Table . Thus, tControls and HTN did not differ in volumes and stroke volume indices  vs. controls . Twenty two percent HTN patients (13 out of 60) had both E/A ratio < 1.12 (Control mean E/A-1SD) and THA > 0.12 (Control mean THA + 1SD) as shown in Figure This study provides a novel approach utilizing normalized torsion shear angle volume HTN is one of the most important risk factors for developing diastolic dysfunction and heart failure. This is attributed to maladaptive concentric LV remodeling, disorganization of sarcomeres, alteration in calcium handling, and increase in extracellular matrix . Our HTNIn the current study, we find that peak early diastolic A number of echocardiographic parameters have been proposed for evaluating diastolic function , such asPrevious study by Takeuchi M, et al. reported decreased early diastolic LV untwisting rate during isovolumic relaxation period in hypertensive patients utilizing 2D speckle tracking imaging . Due to In conclusion,


IRI). Following an acute episode of sustained myocardial ischaemia, the opening of the mitochondrial permeability transition pore (MPTP) in the first few minutes of reperfusion, mediates cell death. Preventing MPTP opening at the onset of reperfusion using either pharmacological inhibitors [such as cyclosporin A (CsA) ] or genetic ablation has been reported to reduce myocardial infarct (MI) size in animal models of acute IRI. Interestingly, the endogenous cardioprotective intervention of ischaemic conditioning, in which the heart is protected against MI by applying cycles of brief ischaemia and reperfusion to either the heart itself or a remote organ or tissue, appears to be mediated through the inhibition of MPTP opening at reperfusion. Small proof‐of‐concept clinical studies have demonstrated the translatability of this therapeutic approach to target MPTP opening using CsA in clinical settings of acute myocardial IRI. However, given that CsA is a not a specific MPTP inhibitor, more novel and specific inhibitors of the MPTP need to be discovered – the molecular identification of the MPTP should facilitate this. In this paper, we review the role of the MPTP as a target for cardioprotection, the potential mechanisms underlying MPTP inhibition in the setting of ischaemic conditioning, and the translatability of MPTP inhibition as a therapeutic approach in the clinical setting.Mitochondria have long been known to be the gatekeepers of cell fate. This is particularly so in the response to acute ischaemia‐reperfusion injury (http://dx.doi.org/10.1111/bph.2015.172.issue‐8This article is part of a themed section on Conditioning the Heart – Pathways to Translation. To view the other articles in this section visit  ANTadenine nucleotide translocaseCABGcoronary artery bypass graftCsAcyclosporin ACypDcyclophilin DDrp1dynamin‐related protein 1GSKglycogen synthase kinaseIPCischaemic preconditioningIPostischaemic postconditioningIRIischaemia‐reperfusion injuryLVleft ventricularMImyocardial infarctATPMitoKmitochondrial ATP‐sensitive potassium channelMPTPmitochondrial permeability transition poreOMMouter mitochondrial membraneOPA1optic atrophy 1PMIperioperative myocardial injuryPPCIprimary percutaneous coronary interventionRICremote ischaemic conditioningRISKreperfusion injury salvage kinaseROSreactive oxygen speciesSAFEsurvivor activating factor enhancementSTEMIST segment elevation myocardial infarctionVDACvoltage‐dependent anion channelTables of Linkset al., et al., et al., et al., et al., The mitochondria are crucial determinants of cardiomyocyte fate following an episode of acute myocardial ischaemia‐reperfusion injury (IRI). In particular, reperfusing acutely ischaemic myocardium induces the opening of the mitochondrial permeability transition pore (MPTP), an event that mediates cardiomyocyte death by uncoupling oxidative phosphorylation and causing mitochondrial swelling. Preclinical animal studies  channel, inhibits calcium‐induced MPTP opening in adult rat cardiac mitochondria  integrity and maintained mitochondrial function. However, no studies have investigated directly whether the MPTP is a target for cardioprotection in the setting of RIC.The mechanism through which the cardioprotective signal applied to an organ or tissue remote from the heart activates pro‐survival signalling pathways in the heart is not clear. Wang et al.  have sho(1) Passive pathway – ischaemic conditioning modulates factors such as cellular energy status, mitochondrial calcium and phosphate accumulation, oxidative stress, and intracellular pH changes, which are known to affect MPTP opening susceptibility  Active pathway – ischaemic conditioning activates a signalling pathway, which then modifies MPTP opening susceptibility by either interacting with putative components of the MPTP, or by modulating the same factors alluded to in the ‘passive pathway’.The actual mechanism through which the cardioprotective signal elicited by ischaemic conditioning mediates its inhibitory effect on MPTP opening at the time of myocardial reperfusion is not clear. A number of potential mechanisms have been proposed, and these can be broadly divided into two different categories  , IPC may reduce mitochondrial calcium overload during ischaemia and inhibit MPTP opening at reperfusion  at the onset of myocardial reperfusion, can limit MI size  have been linked to the activation of the RISK pathway and in the cases of IPC and IPost the activation of this salvage kinase cascade has been shown to inhibit MPTP opening .The activation of the Akt component of the RISK pathway is known to recruit the eNOS‐NO‐sGC‐cGMP‐PKG pathway and through this cascade , attenuating ROS production, improving glucose‐induced insulin release, preventing acidosis through enhanced coupling of glycolysis and glucose oxidation, and inhibition of fatty acid oxidation  ] or fission to form fragmented mitochondria [regulated by the mitochondrial‐fission proteins  ]  has also been identified as a key enzyme involved in cytoprotection in the heart  hypertension, on cardioprotection  and Cyclosporine and Prognosis in Acute Myocardial Infarction Patients (CIRCUS)  multi‐centre randomized clinical trials are currently investigating CsA therapy in PPCI‐treated STEMI patients.The ongoing CYCLosporinE A in Reperfused Acute Myocardial Infarction (CYCLE)  surgery, subjects the heart to acute global IRI as the heart is put onto and taken off cardiopulmonary bypass. The extent of perioperative myocardial injury (PMI) can be quantified by measuring the release into blood of cardiac enzymes, such as creatine kinase and Troponin T or I, the release of which has been linked to worse clinical outcomes. We have recently found that administering a single dose of CsA prior to CABG surgery reduced the extent of PMI in CABG surgery patients  underlying cardioprotection by ischaemic conditioning remains unclear, evidence suggests that it prevents MPTP opening at the reperfusion by modulating factors known to MPTP opening at this time, such as cellular energetic status, mitochondrial CaNone.


Hypertension is a major and correctable cardiovascular risk factor. The correct diagnosis of hypertension and precise assessment of cardiovascular risk are essential to give proper treatment in patients with hypertension. Although echocardiography is the second-line study in the evaluation of hypertensive patients, it gives many clues suggesting bad prognosis associated with hypertension, including increased left ventricular (LV) mass, decreased LV systolic function, impaired LV diastolic function, and increased left atrial size and decreased function. Along with conventional echocardiographic methods, tissue Doppler imaging, three-dimensional echocardiography, and strain echocardiography are newer echocardiographic modalities in the evaluation of hypertensive patients in the current echocardiographic laboratories. Understanding conventional and newer echocardiographic parameters is important in the diagnosis and assessment of cardiovascular risk in hypertensive patients. Cardiovascular diseases are major leading health problems in the world , and hypAlthough the echocardiographic examination is usually recommended as a second-line study in the evaluation of hypertensive patients, it is one of most commonly used imaging modality and has given insights into pathophysiology and clinical implications in patients with hypertension. It can detect anatomical and functional changes easily in a real-time, quick, and reproducible manner. Echocardiography is more sensitive for the detection of asymptomatic organ damage that can be used as a determinant of cardiovascular risk. So, it is important in the clinical management in selected hypertensive patients.In this review, we want to describe the role of echocardiography in the evaluation of hypertensive patients.In the 2013 ESH/ESC Guidelines for the management of arterial hypertension, echocardiography is the second-line study based on medical history, physical examination, and findings from routine laboratory tests ,1615,16]Rapid and reliable assessment of LV systolic function is another advantage of the echocardiography. Although coronary artery disease is the most common cause of LV systolic dysfunction, arterial hypertension is a possible cause of functional impairment of the LV. Echocardiography can give information about the possibility of coronary artery disease in addition to calculation of LV function.Several echocardiographic indices have been introduced to estimate LV systolic function. Among them, LVEF is the most used and the most practical systolic index that has been used as a prognostic factor in various cardiovascular diseases ,17. It cThree-dimensional echocardiographic measurements of LV volumes have been available with technical improvement Figure B 19-21]-2119-21]Because impairment of LV long-axis function occurs at the early stages in many cardiac diseases, its assessment provides a very useful index in the evaluation of hypertensive patients . The LV Tissue Doppler imaging is the new echocardiographic modality to measure mitral annular movement. Mitral annular velocity was decreased in hypertensive patients with normal ejection fraction , and it Myocardial strain can detect subclinical organ damage earlier than other conventional echocardiographic parameters. Kang et al.  reportedThree-dimensional strain echocardiography has been developed by technological advancement, and it can track the motion of myocardial speckles stereoscopically . AnalysiDiastole is a period to fill the LV, and normal diastolic function is required to fill the cardiac chambers without abnormally elevated pressure . The diaAlthough LV diastolic dysfunction is associated with increased mortality in middle-aged and elderly adults , the estEchocardiography is a useful imaging tool to measure LV diastolic function. Several echocardiographic modalities can be used to estimate LV filling pressure. Increased LA size and volume is one of indicator of increased LV filling pressure ,45. EnlaMitral inflow pattern by pulsed-wave Doppler technique is another maker of diastolic function Figure A. IsovolMitral annular velocity can be assessed by pulsed-wave Doppler of mitral annulus from tissue Doppler imaging Figure B. BecausHowever, the E/e’ ratio has pitfalls in the assessment of LA filling pressure . The E/eDiastolic stress echocardiography using exercise stress can detect hemodynamic consequences of exercise-induced increase in diastolic filling pressure noninvasively . It can LA enlargement is commonly associated with systemic arterial hypertension in patients without significant valvular heart disease, and it is associated with overweight, LVH, and metabolic syndrome . LA size2 [2 is associated with poor prognosis including death, heart failure, atrial fibrillation, and ischemic stroke [LA volume can be assessed by two-dimensional echocardiography Figure . Normal 2 , and enl2 . Volume c stroke ,57. BecaLA function is important in the regulation of LV filling by reservoir, conduit, and booster pump functions . LA reseTwo-dimensional speckle-tracking echocardiography has been used in the assessment of LA function in a noninvasive, simple, and reproducible manner . HyperteAnalysis of LA appendage can give indirect information about LA function, and impaired LA appendageal function in patients with non-dipper compared to dipper hypertensive patients . AlthougThree-dimensional echocardiography has been introduced in the measurement of LA size and volume, and it gives many advantages over two-dimensional echocardiography . Real-tiSecondary pulmonary hypertension can be resulted from increased LA pressure transmitted to pulmonary circulation. Also, HF with preserved ejection fraction is a common cause of pulmonary hypertension . EchocarWhere PASP is the pulmonary artery systolic pressure, RVSP is the right ventricular systolic pressure, TR Vmax is the maximal tricuspid regurgitant velocity, and RAP is the right atrial pressure.Right ventricular outflow tract acceleration time is the time from the beginning of the right ventricular ejection until the maximum of the systolic velocity . This acBecause systemic arterial hypertension is also a risk factor of atherosclerosis, atherosclerotic heart diseases can be seen during echocardiographic examination. Ischemic heart disease, dilatation of ascending aorta, and aortic valve sclerosis or stenosis can be found. Presence of regional wall motion abnormalities or ventricular aneurysm is associated with ischemic coronary artery diseases. Stress echocardiography with using exercise protocol or dobutamine stress can detect ischemic heart diseases more sensitively. Dilatation of ascending aorta is associated with increased arterial stiffness and LV mass, and its reported incidence was 17% in hypertensive patients . CalcifiBecause echocardiography can detect cardiac morphologic and hemodynamic change caused by systemic arterial hypertension, echocardiography is a powerful tool for the evaluation of target organ damage, which is essential for the evaluation of cardiovascular risk. Although echocardiography is not an essential first-line imaging study, echocardiography is an excellent tool for the assessment of future cardiovascular risks. Because of its non-invasiveness and easy accessibility, it is also a widely and most commonly used imaging modality in the cardiology practice. However, conventional echocardiography has many pitfalls in the interpretation of several echocardiographic parameters. To overcome this limitation, physicians should be aware of the pitfalls of conventional echocardiographic parameters. Second, doctors should analyze and interpret echocardiographic findings in conjunction with other findings from physical examination and routine examinations. Third, it is worthwhile for medical practitioners to learn other newer echocardiographc modalities. Aside from conventional echocardiographic modalities, newer echocardiographic methods including tissue Doppler imaging, strain echocardiography, or three-dimensional echocardiography also have been introduced to evaluate hypertensive patients providing valuable information about the extent of cardiac damages thus helping us to give better treatment.


Pulmonary arterial hypertension (PAH) is characterized by RV dysfunction. However, abnormal ventricular interactions also result in abnormalities of systolic and diastolic LV function. Unfortunately, these changes may be subtle and are often overlooked in clinical assessment. In this study, a novel self-gated tissue phase mapping (TPM) sequence was used to evaluate the components of LV motion in patients with PAH. The aim was to better characterize abnormal LV function and to assess its functional significance.The study population consisted of 20 patients with PAH and 20 age- and sex-matched healthy volunteers. All patients underwent a 6-minute walk and NT-proBNP testing, and 12 patients underwent right heart catheterization within 1 calendar month of the CMR. A self-navigated retrospectively gated golden-angle spiral sequence was used to perform TPM of basal- and mid-ventricular slices. The raw TPM data was used to calculate radial, tangential (twist) and longitudinal myocardial velocities for the two LV slices. In addition, all patients underwent conventional LV and RV volumetric assessment.The LVEDV was lower in PAH with preserved ejection fraction compared to normal controls. TPM revealed significant abnormalities of systolic and diastolic motion in both the basal and mid LV cavities of patients with PAH table  Figure 1We have shown using a novel TPM sequence that there are significant abnormalities of LV systolic tangential and diastolic radial and longitudinal velocities in PAH. Furthermore, we have demonstrated that there is temporal distortion of the separate components of early diastolic LV motion. Importantly, we have shown that these abnormal measures correlate with 6-minute walk distances, implying that part of reduced exercise tolerance in PAH is secondary to LV disease. In fact, the only independent predictor of the 6-minute walk test was the radial e-wave, which suggests that LV early diastolic dysfunction may play a pivotal role in the disease symptoms.Drs. Daniel Knight and Vivek Muthurangu are funded by the British Heart Foundation (BHF).


Myocardial perfusion was estimated based on the product of microvascular filling velocity and blood volume. WD-feeding resulted in a prediabetic phenotype characterized by obesity, hyperinsulinemia, hyperlipidemia, glucose intolerance, and hyperglycemia. At baseline, WD-feeding impaired myocardial perfusion and systolic function compared to CD-feeding. Exposure of healthy rats to sevoflurane increased the microvascular filling velocity without altering myocardial perfusion but impaired systolic function. In prediabetic rats, sevoflurane did also not affect myocardial perfusion; however, it further impaired systolic function. Diet-induced prediabetes is associated with impaired myocardial perfusion and function in rats. While sevoflurane further impaired systolic function, it did not affect myocardial perfusion in prediabetic rats. Our findings suggest that sevoflurane anesthesia leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state.Preservation of myocardial perfusion during surgery is particularly important in patients with increased risk for perioperative complications, such as diabetes. Volatile anesthetics, like sevoflurane, have cardiodepressive effects and may aggravate cardiovascular complications. We investigated the effect of sevoflurane on myocardial perfusion and function in prediabetic rats. Rats were fed a western diet (WD;  Myocardial perfusion in relation to myocardial function determines the balance between myocardial energy supply and demand. During surgery, maintenance of myocardial oxygen balance is challenged. Extrinsic factors, like anesthetics and surgical stress, and intrinsic factors, such as cardiometabolic disease, affect myocardial oxygen supply and consumption. This altered balance may increase the vulnerability of the heart for an oxygen supply and demand mismatch and consequent ischemia , 2.The volatile anesthetic sevoflurane exerts direct effects on the heart and circulation that jeopardise perioperative myocardial function and hemodynamic stability. Sevoflurane has vasodilating properties and is known to reduce coronary vascular resistance  and perfWhile sevoflurane exerts contrasting effects on myocardial perfusion in healthy conditions, its vasodilatory impact may be more abundant in patients with cardiometabolic disease, like type 2 diabetes mellitus (T2DM). T2DM patients are more likely to develop coronary artery disease  and haveTherefore, the purpose of the present study was to investigate the additional effect of sevoflurane anesthesia on myocardial perfusion and function in diet-induced prediabetic rats. We hypothesized that the impact of sevoflurane anesthesia is more abundant in the presence of cardiometabolic disease and thereby challenges perioperative regulation of myocardial perfusion and function.This study was carried out in strict accordance with the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes. All experiments were approved by the Institutional Animal Care and Use Committee of the VU University (permit number ANES 12-04) and performed in compliance with the modern ARRIVE guidelines on animal research . All surn = 8) or control diet . After 8 weeks of diet exposure, rats underwent an oral glucose tolerance test. Rats were sacrificed after a 6 h fasting period by decapitation and trunk blood was collected for plasma determinations.The study was divided into two parts: (1) characterization of the phenotype induced by western diet feeding and (2) myocardial perfusion and function measurements during baseline conditions and sevoflurane exposure. The first part of the study was performed in a group of 16 male Wistar rats , which were exposed to a western diet in combination with sucrose water (20%)  or WD (n = 18) as described above. After 8 weeks, rats underwent (contrast) echocardiography during baseline conditions and after 5 minutes of sevoflurane (2.0%) exposure.The second part of the study included 36 male Wistar rats  that were exposed to either CD  under a 12/12 h light/dark cycle starting at 6.00 a.m. Body weight and caloric intake were determined on a weekly basis.CD  consisted of 20% kcal protein, 9% kcal fat, and 74% kcal carbohydrates , whereas WD  consisted of 20% kcal protein, 45% kcal fat, and 35% kcal carbohydrates  with 20% sucrose water , totally containing 3300 kcal/kg and 4857 kcal/kg for CD and WD with sucrose water, respectively.Part 1In the first part of the study, awake rats fasted overnight received an oral glucose load (2 g/kg of body weight). Blood glucose was measured from tail bleeds with a Precision Xceed Blood Glucose monitoring system  before (0) and 15, 30, 60, 90, and 120 min after glucose ingestion. At similar time points, plasma insulin  levels were measured as described previously , 21.Plasma hematocrit levels were determined using microcentrifugation. Plasma glucose levels , plasma insulin , plasma free fatty acids , plasma triglyceride , and plasma HDL and LDL/VLDL cholesterol  levels were measured from trunk blood as described previously , 21, 22.Part 22O; respiratory rate, ~65 breaths/min; tidal volume, ~10 mL/kg) with oxygen-enriched air (40% O2/60% N2). Anesthesia was maintained by continuous infusion of 50 mg/kg/h S-Ketamine and 1.3 mg/kg/h diazepam intravenously via the tail vein. Respiratory rate was adjusted to maintain pH and partial pressure of carbon dioxide within physiological limits. Body temperature was maintained stable (36.7 ± 1.2°C) using a warm water underbody heating pad.The rats in the second part of the study were anesthetized with 125 mg/kg S-Ketamine  and 4 mg/kg diazepam  intraperitoneally. The trachea was intubated and lungs were mechanically ventilated , and measurements of arterial blood pressure . Arterial blood pressure, ECG, and heart rate were continuously recorded using PowerLab software . Mean arterial blood pressure was calculated according the following formula: 2/3 · diastolic  blood  pressure + 1/3 · systolic  blood  pressure. Rate pressure product (RPP) was calculated by the product of heart rate and systolic blood pressure and was used as an estimate of myocardial oxygen demand.sn-glycero-3-phosphocholine  and polyoxyethylene stearate  were dissolved in glycerol (10 mg/mL) and sonicated  at 40 kHz in an atmosphere of perfluorobutane  and vials were shaken in a Vialmix at 4500 rpm . As the gas was dispersed in the aqueous phase, microbubbles were formed, which were stabilized with a self-assembled lipid/surfactant monolayer. Freshly made bubbles were then washed twice to remove excessive DSPC and PEG40 and stored refrigerated in sealed vials in perfluorobutane atmosphere. A Multisizer 3 Coulter Counter  was used to measure the particle size distribution as well as the number of particles. The average bubble concentration was 1.58 · 109 ± 0.36 · 109 and the particle range was between 1 and 10 μm. Microbubbles were diluted to a concentration of 200 · 106 with degassed NaCl.Microbubbles were prepared from perfluorobutane gas and stabilized with a monolayer of distearoyl phosphatidylcholine and PEG stearate. 1,2-Distearoyl-μL/min using a dedicated syringe pump . After two minutes of microbubble infusion, perfusion images were taken from the long-axis view of the left ventricle.After surgery (contrast) echocardiography was performed to determine myocardial function and perfusion during baseline conditions and after 5 minutes of sevoflurane (2%) exposure. Contrast echocardiography was performed using a Siemens  equipped with a 14 MHz linear array transducer , 14. MicLow acoustic power  was used for microbubble detection with a dynamic range of 50 dB. A perfusion sequence consisted of about 10 cardiac cycles of low MI imaging, followed by a burst of high acoustic power (MI 1.8) for complete contrast destruction. Subsequently, on average 20 cardiac cycles of low MI images were acquired to allow contrast replenishment in the myocardium. All data were stored for offline analysis.Y0). These intensities were then fitted (Y = Y0 + (A − Y0)·(1 − expβ·x)(−)) for calculation of microvascular blood volume A and the microvascular filling velocity β, which corresponds to the capillary blood exchange rate. The estimate of perfusion was calculated as the product of A and β [Custom-designed software was used for analysis of the estimate of perfusion  , 14. For A and β .2 − ESD2)/EDD2 · 100. All parameters were averaged over at least three cardiac contractile cycles.Myocardial systolic function was determined with echocardiography , 14. Brit-test, whereas the effect of sevoflurane was tested with a two-way ANOVA with Bonferroni as post hoc test. p < 0.05 was considered as statistically significant.Data were analyzed using Graphpad Prism 5.0  and presented as mean ± SD. Between group comparisons (CD versus WD) were performed using a Student Eight weeks of western diet feeding resulted in a mild type 2 diabetic (prediabetic) phenotype with obesity, mild hyperglycemia, hyperinsulinemia, hyperlipidemia , and gluβ) and significantly decreased microvascular blood volume (A), which resulted in a significant reduction in the estimate of perfusion  and tended to increase microvascular blood volume (A) in controls, while this observation was absent in western diet-fed animals. Overall, this resulted in an unchanged estimate of perfusion in both diet groups , which was associated with impaired myocardial perfusion and systolic dysfunction. Sevoflurane had no additional effect on myocardial perfusion in healthy and prediabetic rats, while it impaired systolic function in healthy rats and even further impaired systolic function in prediabetic rats. These results suggest that sevoflurane leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state.An interesting finding in this study is that myocardial perfusion and function were both decreased in diabetic rats compared to healthy controls. Previously, we found that myocardial perfusion and function were unaffected in high fat diet-induced glucose intolerant rats compared to healthy controls . In the α-chloralose [β) and increased microvascular blood volume (A). The microvascular filling velocity is a parameter of the capillary exchange rate providing an estimate of the speed of erythrocytes through the capillaries, while microvascular blood volume suggests the surface area for exchange of nutrients and correlates with oxygen consumption. Our observations are in contrast with a previously performed study in cardiovascular healthy subjects by our group, where we showed that sevoflurane decreased myocardial blood volume and increased the microvascular filling velocity [During surgery, the balance between myocardial energy supply and demand is challenged by extrinsic factors such as anesthetics. The volatile anesthetic sevoflurane exerts contrasting effects on myocardial perfusion in healthy animals and subjects. Previously it has been shown that sevoflurane did not alter myocardial blood flow in healthy rats  and cardloralose , dogs anloralose , and awaloralose . The prevelocity . A possivelocity . Howevervelocity  or unchavelocity  heart ravelocity , adminisvelocity , 27, thiPreservation of myocardial perfusion during surgery is particularly important in patients with increased risk for perioperative cardiac complications, such as diabetes. Recently, our group showed that sevoflurane decreased myocardial perfusion in type 2 diabetic patients compared to healthy controls. Moreover, we observed a trend towards a lower endothelium-independent vasodilation capacity in type 2 diabetic patients under sevoflurane anesthesia, while endothelium-dependent vasodilation was not affected . Our preIn conclusion, sevoflurane anesthesia maintained myocardial perfusion, while it impaired systolic function in healthy rats and even further impaired systolic function in prediabetic rats. Our findings suggest that sevoflurane anesthesia uncouples myocardial function and myocardial perfusion, irrespective of the metabolic state. This uncoupling might increase the vulnerability of the heart for an oxygen supply and demand mismatch and consequent ischemia during surgery.


To assess the early effects on myocardial function, reversible and irreversible myocardial injury of both transcatheter (TAVI) and open aortic valve replacement (AVR) utilizing cardiovascular magnetic resonance (CMR) and biochemistry. Although recent studies have reported on clinical outcomes, there has been a paucity of mechanistic data on the effect of TAVI on ventricular function and irreversible myocardial injury.We conducted a prospective comparative study of 47 patients  with severe aortic stenosis and normal or mildly impaired ventricular function undergoing either TAVI or high risk AVR. CMR  was carried out pre- and early post-operatively ( < 2 weeks). Biochemistry, high-sensitivity troponin and Pro B-type natriuretic peptide, and transthoracic echocardiography were also performed.Groups were similar with respect to STS Score (TAVI 7.7 vs AVR 5.9 p = 0.11) and comorbidities, however the TAVI group were older . Preoperative left ventricular (LVEF: TAVI 69% ± 13 vs AVR 73% ± 10 p = 0.10) and right ventricular ejection fractions (RVEF: TAVI 61% ± 11 vs AVR 59% ± 8 p = 0.5) were similar. Post-operative LVEF was preserved in both groups. In contrast, a decline in RVEF was notably more significant in the TAVI group . Further analysis showed a trend (p = 0.08) association between the degree of post-procedure aortic regurgitation and RV dysfunction. There were no differences in the rate of reversible (T2)irreversible (LGE) injury.There was no significant difference in early left ventricular systolic function between open and transcatheter techniques, matched by similar myocardial injury rates. While RV systolic function was preserved in the AVR group, it was significantly impaired early after TAVI, correlating with the degree of para-valvular aortic regurgitation.Funding was provided in the form of unencumbered research grants from St Jude Medical and Edwards Lifesciences.


Long noncoding RNAs (lncRNAs) are non-protein coding transcripts regulating a variety of physiological and pathological functions. However, their implication in heart failure is still largely unknown. The aim of this study is to identify and characterize lncRNAs deregulated in patients affected by ischemic heart failure.LncRNAs were profiled and validated in left ventricle biopsies of 18 patients affected by non end-stage dilated ischemic cardiomyopathy and 17 matched controls. Further validations were performed in left ventricle samples derived from explanted hearts of end-stage heart failure patients and in a mouse model of cardiac hypertrophy, obtained by transverse aortic constriction. Peripheral blood mononuclear cells of heart failure patients were also analyzed. LncRNA distribution in the heart was assessed by in situ hybridization. Function of the deregulated lncRNA was explored analyzing the expression of the neighbor mRNAs and by gene ontology analysis of the correlating coding transcripts.h19, rmrp and hotair were also induced in a mouse model of heart hypertrophy. CDKN2B-AS1/ANRIL, HOTAIR and LOC285194/TUSC7 showed similar modulation in peripheral blood mononuclear cells and heart tissue, suggesting a potential role as disease biomarkers. Interestingly, RMRP displayed a ubiquitous nuclear distribution, while H19 RNA was more abundant in blood vessels and was both cytoplasmic and nuclear. Gene ontology analysis of the mRNAs displaying a significant correlation in expression with heart failure lncRNAs identified numerous pathways and functions involved in heart failure progression.Fourteen lncRNAs were significantly modulated in non end-stage heart failure patients, identifying a heart failure lncRNA signature. Nine of these lncRNAs  were also confirmed in end-stage failing hearts. Intriguingly, among the conserved lncRNAs, These data strongly suggest lncRNA implication in the molecular mechanisms underpinning HF.The online version of this article (doi:10.1186/s12967-016-0926-5) contains supplementary material, which is available to authorized users. It is estimated that heart failure (HF) is the cardiovascular disease with the worse rate of morbidity, mortality, accounting for one of the highest health care costs in the western world. Indeed, the 1-year-survival rate of patients with end-stage HF is about 50 % . Among these, 8 LV samples were collected by an expert pathologist from explanted hearts of patients that underwent cardiac transplantation; the remaining 3 end-stage samples were collected during the implantation of LV assist device (LVAD). Care was taken to avoid necrotic or fibrotic areas. Samples of ~2 mmThe control group was composed by age- and sex-matched subjects, who had died for causes different from stroke, ischemia, or cachexia for chronic diseases . Left ventricle samples were excised and processed with less than 30 min cold ischemic time and snap frozen .All experimental procedures complied with the Guidelines of the Italian National Institutes of Health and with the Guide for the Care and Use of Laboratory Animals  and were approved by the institutional Animal Care and Use Committee (IACUC n. 709). TAC was performed in 2 months old C57BL/6 J male mice with a 27-gauge needle . Before Genomic DNA was isolated from twenty 10 μm-thick paraffin-embedded tissue sections. Following deparaffinization twice for 5 min in xylene, DNA was extracted using QIAamp DNA FFPE Tissue kit  following manufacturer’s instructions. Four CDKN2-AS SNPs  were assessed by TaqMan SNP Genotyping Assay on ABI 7900 real time PCR platform . 20 ng of DNA were amplified in a reaction volume of 25 μl, containing 12.5 μl of 2× TaqMan Master Mix, 1.25 μl of 20× Assay working stock solution and 6.25 μl of nuclease-free water. Real time PCR conditions were: one cycle of 2 min at 50 °C, one cycle of 10 min at 95 °C; 40 cycles of 15 s at 95 °C and 1 min at 60 °C.http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE77399). After median Ct value normalization, relative RNA expression was calculated with the 2−ΔΔCt method [−ΔΔCt fold change ≥|1| were used for further validation. Validation was carried out with newly designed specific primers by SYBR-GREEN qPCR  as described previously , 22. Sizt method . SignifiIn situ hybridization was performed using the QuantiGene ViewRNA system (Affymetrix) according to the manufacturer’s instructions. Briefly, 3-μm-thick sections were derived from FFPE-embedded biopsies and mounted on Superfrost Plus Gold glass slides (Thermo Fisher Scientific). Next, deparaffinized sections were hybridized with oligonucleotide probes conjugated with alkaline phosphatase (LP-AP) type 1, followed by staining with fast blue substrate, counterstaining with Hoechst 3332 (Sigma-Aldrich Co.) and mounted with VectaMount AQ medium .To identify endothelial cells, serial LV sections were deparaffinized, microwave-treated and incubated with anti-human CD31 mouse monoclonal antibody . After incubation with biotinylated secondary antibodies and with ABC complex (Vectastain), the reaction was revealed with diaminobenzidine  and counterstained with Hematoxylin.For both in situ hybridization and immunohistochemistry, at least two blinded readers carried out the analysis and random images were acquired using an Axio Imager M.1 microscope equipped with an Axiocam MRc5 camera (Zeiss) and AxioVision software (Zeiss).To analyze the relationship between lncRNAs and mRNAs differentially expressed in the same HF samples, we used the dataset GEO GSE26887 . We idenFor neighboring gene analysis, the 300 kb of genomic sequence upstream and downstream the HF modulated lncRNAs were identified by using UCSC Genome Browser (GRCh38/hg38 assembly) . SignifiFor the comparison of transcriptomic changes in LV and PBMCs of HF patients, the following GEO datasets were analyzed: for LV, GSE26887 , and fort test (two groups) were used as appropriate. All tests were performed 2-sided and a p ≤ 0.05 was considered as statistically significant. For statistical analysis, GraphPad Prism v.4.03 software (GraphPad Software Inc.) was used. For CDKN2B-AS SNPs analysis, observed allele frequencies were compared to reported allele frequencies in HapMap–CEU European using an exact multinomial test using R package EMT [Continuous variables are expressed as mean ± standard error. Gaussian distribution was tested by using the Kolmogorov–Smirnov test. For group-wise comparisons, Mann–Whitney test (two groups) or kage EMT .In order to identify lncRNAs deregulated in HF, LV biopsies of 13 HF patients and 12 age-and sex-matched controls were analyzed. Worth noting is that myocardial biopsies were harvested from the non-ischemic portion of the LV (remote zone) in non end-stage HF patients, allowing to investigate the molecular mechanisms underpinning the disease during its progression. As expected, histological analysis revealed cardiomyocyte hypertrophy  is located in a region with several SNPs that correlate to increased genetic susceptibility to coronary artery diseases and type 2 diabetes , 33. In In order to validate the identified HF lncRNA signature, we analyzed 11 RNAs derived from left ventricle samples of patients with chronic ischemic end-stage HF. These patients exhibited more severe clinical conditions and LV dilation compared to the patients used for lncRNA profiling.We found that 9 lncRNAs  were significantly modulated in a concordant manner in both end- and non end-stage HF patients  transcript levels decreased, while natriuretic peptides A and B (nppa and nppb) as well as Actin α1 (acta) transcripts increased in TAC hearts compared to controls  are a particularly attractive biomarker source because of the accessibility of peripheral blood and its straightforward preparation. Furthermore, inflammation and the underlying cellular and molecular mechanisms seem to play a crucial pathological role in the progression toward HF , 39. AccThus, we measured the expression of the HF deregulated lncRNAs in PBMCs from 25 HF patients and 18 healthy individuals by RT-qPCR. Interestingly, we found that CDKN2B-AS1, HOTAIR and LOC285194 showed similar modulation in PBMCs and heart tissue, suggesting a potential as disease biomarkers . However, we were able to detect H19 in left ventricle sections, possibly due to its localized accumulation, mainly interstitial; indeed, the staining of serial sections with H19 and anti-CD31 antibody indicated a likely vascular localization Fig. . AccordiDapB of Bacillus subtilis  .mRNAs and HF lncRNAs were used for correlation analysis, which identified 10,257 and 8852 transcripts displaying significant direct or inverse correlation, respectively, with at least one HF lncRNA  in mammalian , and othAlso interesting is the deregulation of CDKN2B-AS1, HOTAIR and LOC285194 in PBMCs derived from HF patients. Given the importance of inflammation in HF progression , it is tSince peripheral blood can be obtained with minimally invasive procedures, CDKN2B-AS1, HOTAIR and LOC285194 might have a potential as circulating biomarkers of HF. Further studies in larger patients groups are necessary to assess their validity as disease biomarkers.Pathway enrichment analysis highlighted several important cardiovascular categories enriched in HF lncRNAs-correlated mRNAs. Although correlative , this anink4a), which is located in the 50 kb chromosomal locus 9p21 [CDKN2B-AS1 is the antisense gene of CDKN2B  gene generates both steroid receptor RNA activator protein (SRAP) as well as several non-coding SRA transcripts, depending on alternative transcription start site usage and alternative splicing , 65. FriH19 is a developmentally regulated gene with putative tumor suppressor activity . Here weAmong the protein coding genes neighbor to the lncRNAs, it is interesting the concordant modulation of HOTAIR and SMUG1, which is related to free-radicals response . AdditioWe identified 14 lncRNAs that are dysregulated in non end-stage HF patients. Validation in other patient groups and in animal experimental models corroborated the findings, and the deregulation of some of them in the peripheral blood suggests a potential as disease biomarkers. While future investigations of the identified HF lncRNA actions and dysfunctions are required, analysis of the correlated genes indicates their implication in the molecular mechanisms underpinning HF progression.


P < 0.001) and passive emptying index  were remarkably reduced compared to baseline values, while active emptying percent of total emptying  and active emptying index  were increased. GLS (−21.64 ± 2.83 vs. −17.30 ± 2.50) was markedly reduced, cTnT levels was elevated from 0.005 ± 0.004 to 0.020 ± 0.026 ng/mL at the completion of chemotherapy . Early LA functional change occur after doxorubicin exposure in patients with preserved LVEF, which could be detected by RT-3DE.Real-time three-dimensional echocardiography(RT-3DE) has allowed a better assessment of LA volumes and function. We sought to assess the early change in left atrial size and function in patients treated with anthracyclines using RT-3DE. 61 patients aged 44.9 ± 11.9 years with large B-cell non-Hodgkin lymphoma treated with doxorubicin were studied. Blood collection and echocardiography were performed at baseline and 1 day after completion of the chemotherapy. Global longitudinal strain (GLS), maximum, minimum and pre-atrial contraction LA volumes were measured and reservoir, conduit and booster pump function were assessed. Despite normal LVEF, passive emptying percent of total emptying (0.51 ± 0.14 vs. 0.40 ± 0.12,  Anthracyclines chemotherapy remains a critical component of cancer treatment despite its established risk of cardiotoxicity. It has been suggested that diastolic changes precede systolic dysfunction in various conditions and predict later deterioration12478In our study we sought to assess the early change in left atrial size and function in patients treated with anthracyclines using three-dimensional echocardiography.A total of 66 patients with newly diagnosed, histopathologically confirmed large B-cell non-Hodgkin lymphoma in fudan university shanghai cancer center were enrolled in this study between March 2012 and May 2015. Age < 18 years, left ventricular ejection fraction (LVEF) <50%, valvular heart disease, severe hypertension, life expectancy ≤12 weeks, arrhythmia, a previous history of heart failure and/or coronary artery disease were exclusion criteria for enrollment. All patients were treated with R-CHOP , and rituximab 375 mg/m2. All therapy was given intravenously, except for prednisone, which was administered orally. Cycles were administered every 21 days for a maximum of 8 cycles. Rituximab was administered before chemotherapy. Patients were restaged every 2 cycles, and those with disease progression were withdrawn from the treatment of R-CHOP. No patients received other cardiotoxic agents or radiation therapy during this study. All patients gave informed consent, and the Fudan University Shanghai Cancer Center and Zhongshan Hospital Research Ethics Committee approved the protocol. Our study were carried out in accordance with the approved guidelines from the ethics committee.A standard 2DE and RT3DE examination were performed for all patients. All 2DE and RT3DE examinations were performed with a commercially available ultrasound system  equipped with an S5-1 and X3-1 transducer. Measurements were made off line in a dedicated workstation .LV ejection fraction was calculated by means of 2DE, using modified biplane Simpson’s rule. Conventional spectral Doppler variables  and tissue Doppler data  were obtained according to standard guidelines11The automatic tracking analysis was performed in the apical four-chamber, two-chamber, apical LV longitudinal view for longitudinal strain by two-dimensional speckle tracking analysis.th point at apex of LA. Once this is completed, the endocardial surface was automatically delineated and a mathematical model of the LA calculation was obtained. Manual modification was made to correct the automatic tracing if needed , was used to obtain LA volumes and volumetric curves. This is performed by marking 5 points in the atrial surfaces of the mitral annulus: at anterior, inferior, lateral and septal annuli and the 5f needed .The following LA volumes were calculated: maximum atrial volume (LAVmax), the largest atrial volume at end systole; minimal atrial volume (LAVmin), at end diastole; volume before atrial contraction (LAVpre-a), the atrial volume in the last frame before or at time of P-wave. All comparisons between LA volumes were made considering volumes indexed to body surface area. LA reservoir function was assessed by 3 indices. Filling volume was calculated by LAVmax-LAVmin. Expansion index was analyzed by ([LAVmax-LAVmin]/LAVmin) × 100. Diastolic emptying index was determined by ([LAVmax-LAVmin]/LAVmax) × 100. LA conduit function was assessed by calculating the passive emptying percent of total emptying (PE) as ([LAVmax-LAVpre-a]/[LAVmax-LAVmin] × 100 and the passive emptying index (PEI) as ([LAVmax-LAVpre-a]/LAVmax) × 100. Booster pump function was assessed as follows. Active emptying percent of total emptying (AE) was calculated as ([LAVpre-a-LAVmin]/[LAVmax-LAVmin]) × 100. Active emptying index (AEI) was assessed by ([LAVpre-a-LAVmin]/LAVpre-a) × 100All the recorded images were analyzed at different times by two independent echocardiographers. The same images were also analyzed on a different day by one of these same observers.th percentile value in apparently healthy individuals of 0.014 ng/mLBlood was collected into EDTA tubes, centrifuged, and the plasma was removed and stored at −80 °C. The cTnT concentrations were measured with highly sensitive cTnT reagents on an Elecysys 2010 analyser , with a lower detection limit of 0.003 ng/mL and a reported 99Intra- and inter-observer reproducibility was assessed by calculating the difference between the values of 10 randomly selected patients measured by 1 observer twice and by a second observer.Continuous variables were expressed as the mean ± standard deviation. Nominal variables were expressed as percentages. Differences before and after chemotherapy were determined using paired sample t test for continuous variables and Fisher’s exact test for categorical data. Inter- and intra-observer reproducibility of LAV-max, LAV-min, LAVpre-a were assessed using intraclass correlation coefficients (ICCs). Data were analyzed by SPSS version 16.0 . A value of p ≤ 0.05 was considered significant.2 (ranging from 200 to 400 mg/m2). After treatment of R-CHOP, no patient complained of cardiovascular related symptoms. EKG remained normal in all patients.Four patients were excluded from the analysis because of poor image that can not be recognized by the workstation. One died before completion of chemotherapy due to pneumonia and secondary respiratory failure. A total of 61 patients, 34 males, ranging from 20 to 70 years (mean age 44.9 ± 11.9 years) were finally include in the statistical analysis. Cumulative dose of doxorubicin was 258.20 ± 69.03 mg/mSystolic blood pressure and diastolic blood pressure were within normal limits for all patients before and after chemotherapy . Heart rate is markably faster than that before treatment .P < 0.001.Diastolic posterior wall thickness showed no significant difference before and after chemotherapy . Conventional parameters of systolic and diastolic function, including EDV, LVEF, fraction shortening, E velocity, A velocity, E/A ratio, deceleration time, isovolumic relaxation time, average of peak early diastolic velocities (e’), average of peak late diastolic velocities (a’), and E/e’ ratio showed no significant difference after doxorubicin treatment. GLS was significantly reduced after the completion of chemotherapy from −21.64 ± 2.83 to −17.30 ± 2.50, P all  < 0.001).Before doxorubicin exposure, cTnT levels of 13 patients (21.31%) were below the limitation of detection (<0.003 ng/mL). In these participants, after the completion of chemotherapy, cTnT levels became detectable in the whole cohort. In the analysis, undetectable cTnT levels were considered to be 0.0015 ng/mL15P < 0.001), 0.29 ± 0.10 to 0.23 ± 0.06 (P < 0.001), respectively. Active emptying percent of total emptying and active emptying index  were markedly higher than that value before treatment , quite lower than the recommended maximum lift time cumulative doseWe also found that though the mean cumulative dose of doxorubicin in our study was only 258.20 ± 69.03 mg/mCardiac troponin T is the preferred biomarker for the measurement of myocardial injury. It has been demonstrated that low level elevations of cTnT induced by doxorubicin are associated with histological evidence of myocardial injury and are clinically meaningfulSeveral limitations to this study warrant comment. The present study does not provide information on the value of LA volume and function parameters in prognostication. Further out-come studies with hard clinical end points will be required to determine the clinical significance of our findings. Secondly, we used a semiautomated contour-tracing software which was designed for LV volume analysis to obtain LA volumes and volumetric curvesm as a results of lacking dedicated atrial software. Thirdly, we did not include LA appendage and pulmonary veins for calculation of LAV and function. Their variability in shape, its difficulty to measure and the lack for standard figures for its normal volume seems reasonable to exclude it. Finally, there was no normal control group, we analyzed the patients parameters by own control comparison.Early LA functional change occur after doxorubicin exposure in patients with preserved LVEF, which could be detected by RT-3DE. Phasic LA volumes and parameters might provide a earlier expression of anthracycline-induced subclinical cardiotoxicity.How to cite this article: Shi, J. et al. Early change in left atrial function in patients treated with anthracyclines assessed by real-time three-dimensional echocardiography. Sci. Rep. 6, 25512; doi: 10.1038/srep25512 (2016).


Cardiac MR (CMR) is considered the gold standard to assess right ventricular (RV) function in different scenarios, including cases of congenital heart disease. Moreover, an MR-compatible treadmill coupled with Real Time (RT) CMR has been developed for stress testing, and may be an optimal choice in this setting. The aims of this study were to determine the feasibility and accuracy of a RT CMR protocol to evaluate RV function at rest and after treadmill exercise in adults with history of repaired Tetralogy of Fallot (ToF).Ten young adults  were prospectively enrolled, and imaging was performed using a 1.5T scanner  and 32-channel phased array coil. RV cavity was covered by 10 to 12 contiguous 8 mm transverse slices. ECG-Gated SSFP cine was performed at rest , while non-triggered RT cine was executed both at rest and after stress . Patients underwent treadmill exercise with 12-lead ECG  to achieve a goal of ≥ 85% age-predicted maximum heart rate (APMHR). RT cine imaging was performed immediately upon cessation of exercise. End-diastolic (EDV) and end-systolic (ESV) volumes were calculated by two different observers using Simpson's rule by manually tracing RV endocardial borders. Interobserver agreement was analyzed by the Pearson's correlation coefficient whereas differences were assessed with paired t-test .Both ECG-Gated and RT techniques demonstrated excellent interobserver agreements for EDV, ESV, and ejection fraction (EF) , indicating good reproducibility. Average results between the two observers are listed in Table The feasibility of RT CMR imaging coupled with treadmill exercise was demonstrated. The diagnostic value of this technique to assess RV function in patients with repaired ToF deserves further assessment in a larger patient cohort.Partially funded by NIH: R01 HL102450.


Studies regarding the association between prehypertension and the structual changes of left heart are scanty. However, which type of the geometrical change of left heart is predominated one in prehypertension and hypertension is controversial. It is therefore important to investigate geometrical and functional changes of left heart in adults with prehypertension and hypertension because of their prognostic significance.The study was based on a cross-sectional design, a total of 10547 participants were classified into normotension group, prehypertension group and hypertension group. We analyzed clinical characteristics, echocardiographic parameters and distribution of left ventricular (LV) geometrical patterns in different groups.P <0.001), and the rates of LVH in the three groups were 5.9, 8.6, 28.4 % by indexation to height2.7 and 4.9, 5.3, 19.3 % by indexation to BSA, respectively. The prevalence rates of eccentric hypertrophy, concentric remodeling and concentric hypertrophy were 7.3 %, 5.3 % and 1.4 % in prehypertension group, and 17.8 %, 8.8 % and 10.6 % in hypertension group. Logistic regression analysis showed that systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean artery pressure (MAP) were all independent risk factors for left cardiac structural changes, and pulse pressure (PP) was independent risk factor for concentric and eccentric hypertrophy. Among four indices, DBP levels with OR values of 1.192, 1.759 and 1.278 were the strongest indicator for concentric remodeling, concentric hypertrophy and eccentric hypertrophy, respectively (P <0.001).Participants with prehypertension had higher values of most of echocardiographic parameters than those with normotension. The prevalence of left ventricular hypertrophy(LVH) was statistically different among three groups (There exists LV geometrical change in adults with prehypertension and hypertension in rural Chinese population, and the eccentric hypertrophy was the highest proportion of geometric alterations. SBP, DBP, MAP and PP were all positively associated with left cardiac structural changes, and the association of DBP was the strongest. The type of LV geometrical change is determined mainly by the predominating type of stimulus to the myocardium, volume overload or pressure overload in hypertension . SystoliLiaoning Province is located in Northeast China. From January 2012 to August 2013, a representative sample aged ≥ 35 years was selected to describe the prevalence, incidence and natural history of cardiovascular risk factors in rural areas of Liaoning Province. The study adopted a multi-stage, stratified randomly cluster-sampling scheme. In the first stage, 3 counties  were selected from the eastern, southern, and Northern region of Liaoning province. In the second stage, one town was randomly selected from each county . In the third stage, 8–10 rural villages from each town were randomly selected . Participants with pregnancy, malignant tumor and mental disorder were excluded. All the eligible permanent residents aged ≥ 35 years from each village were invited to attend the study . Of those, 11956 participants agreed and completed the present study and the response rate was 85.3 %. The study was approved by the Ethics Committee of China Medical University . All procedures were performed in accordance with the ethical standards. Written consent was obtained in all participants after they had been informed of the objectives, benefits, medical items and confidentiality agreement of personal information. If the participants were illiterate, we obtained the written informed consents from their proxies. In this report, subjects were excluded if they met any of the following criteria: congenital heart disease, cardiac tumor, myocardial infarction, pericardia disease, cardiomyopathy or other organic heart disease, all kinds of serious arrhythmia, heart valve disease . Finally, a total of 10547 participants were available for analysis, 3616 subjects with prehypertension, 5280 patients with hypertension and 1651 participants with normotension.According to American Heart Association protocol, BP was measured three times at 2 min intervals after at least 5 min of rest using a standardized automatic electronic sphygmomanometer HEM-907; Omron), which had already been validated according to the British Hypertension Society protocol  + 0.6 g.Left ventricular mass (LVM) was estimated by Devereux’ s formula according to the American Society of Echocardiography simplified cubed equation . LVM = 02.7 and body surface area (BSA) to obtain left ventricular mass index (LVMIht2.7 and LVMIBSA). LVH was diagnosed using the following defining criteria  × 100 % and LV fractional shortening (FS) was calculated as [(LVIDd-LVIDs)/LVIDd] × 100 %. All Doppler echocardiographic recordings were registered with 100 mm/s and performed in expiration. Examinations of mitral inflow were performed by pulsed wave Doppler with the sample volume at the mitral valve leaflet tips in the apical four-chamber view and early transmitral diastolic peak flow (E) and atrial peak flow (A) and E/A ratio were determined .Fasting blood samples were collected in the morning after at least 12 h of fasting for all participants. Blood samples were obtained from an antecubital vein into Vacutainer tubes containing EDTA. Fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), plasma creatine (PC), uric acid (UA) and other routine blood biochemical indexes were analyzed enzymatically on an autoanalyzer. All laboratory equipment was calibrated and blinded duplicate samples were used.χ2-test as appropriate. Multivariate logistic regression analyses were used to identify independent factors of SBP, DBP, MAP, and PP with odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) calculated. All the statistical analyses were performed using SPSS version 17.0 software, and P values less than 0.05 were considered statistically significant.Continuous variables were presented as the means and standard deviation (SD), and categorical variables were expressed as numbers or percentages. Differences among categories were evaluated using ANOVA, non-parametric test or the As shown in Table P <0.05). Among the three subgroups, hypertension group had the highest IVSd, PWTd, LVIDd, LVIDs, LVM, LVMI, RWT, AOD, LAD, LAD/BSA, A wave, LVEDV, LVESV and SV, and the lowest E wave, E/A, LVEF and FS (P <0.001). The prevalence of LVH was statistically different among three groups (P < 0.001), and the rates of LVH in the three groups were 5.9, 8.6, 28.4 % by indexation to height2.7 and 4.9, 5.3, 19.3 % by indexation to BSA, respectively (Table Compared with the normotension group, LVIDd, LVIDs, LVM, LVMI, AOD, LAD, LAD/BSA, A wave, LVEDV, LVESV and SV were significantly higher, while E wave and E/A were significantly lower in prehypertension group (Classification of LV geometry showed that the eccentric hypertrophy was the highest proportion of geometric alterations in hypertension and prehypertension groups.in the present study population. The prevalence rates of eccentric hypertrophy, concentric remodeling and concentric hypertrophy were 7.3 %, 5.3 % and 1.4 % in prehypertension group, and 17.8 %, 8.8 % and 10.6 % in hypertension group (Table After adjustment for age, gender, race, height, weight, WC, heart rate, smoking, drinking, salt, degree of physical labor and education, TG, TC, HDL-C, LDL-C, FPG, PC, hemoglobin and UA and antihypertensive medication, logistic regression models were performed to estimate the relationship of four BP indices with LV remodeling in prehypertension and hypertension groups. Results showed that SBP, DBP and MAP were all independent risk factors for left cardiac structural changes, and PP was independent risk factor for concentric and eccentric hypertrophy. Among four BP indices, DBP was the strongest indicator for LV remodeling Table .Table 4M2.7 than to BSA in our study. BSA has been widely used to normalize LVM, however, this does not correctly identify pathological LV hypertrophy in all people, especially when body composition is altered, or in different ethnic groups and may not account for the resultant variation in LVM. Indexation by height2.7 may be considered a more suitable approach to scaling LVM for body size in recent years, especially in obese and overweight hypertensive patients, to some extent independently from the cut-off settled. Considering the presence of a significative difference in BMI between the three groups in our study, we indexed LVM by height2.7 to classify LV geometry in order to minimize the interference of obesity [Our research showed that LV remodeling was found in prehypertension group. Although there were no significantly differences in IVSd, PWTd, RWT between prehypertension and normotension group, the values of LVIDd, LVIDs, LVMI, LVEDV, LVESV and SV that reflect ventricular volume indexes were significantly higher in prehypertension group than normotension group, which suggested that there existed cardiac enlargement, LV remodeling and increased LV volume in prehypertensive status. However, hypertension can produce more obvious myocardial cell compensatory enlargement, LV hypertrophy, LV remodeling and volume increases . The pre obesity –21. Impa obesity . Our stuAccording to LV hemodynamic changes, LV geometrical change can be classified into three types: concentric remodeling, concentric hypertrophy and eccentric hypertrophy. This is determined to a large extent by whether pressure or volume overload is predominating. Approximately 7.3 % of prehypertensive participants and 17.8 % of hypertensive ones in our study had eccentric hypertrophy which was the highest proportion of abnormal geometrical changes in the our study population. On the one hand, the high prevalence of eccentric hypertrophy may be related to the status of volume overload which play a key role in LV adaptations in hypertension or the high prevalence of obesity –25. On tResults from multivariate logistic regression analysis showed that SBP, DBP, MAP and PP were all positively associated with left cardiac structural changes. DBP was the strongest risk factor for concentric remodeling, concentric hypertrophy and eccentric hypertrophy. Thus, it reminds us to strengthen the control of hypertension and pay more attention to prehypertensive status, in order to delay the cardiac damage and the onset of heart failure .This study has some limitations. First, our data is a referral and not a general adult population throughout China. Second, although we made extensive efforts to standardize measurements using the same echocardiographic criteria, subtle differences in performance technique among doctors could still influenced results. In addition, our results were based on a cross-sectional design, thus we are unable to assess the duration of hypertension and antihypertensive medication exactly.2.7 than to BSA. The eccentric hypertrophy was the commonest abnormal geometrical pattern in our study and LV geometrical changes were more likely to be females. SBP, DBP, MAP and PP were all positively associated with left cardiac structural changes, and the association of DBP was the strongest.In this study, there existed LV remodeling and geometrical change in prehypertensive status, and more obvious myocardial cell compensatory enlargement, LV hypertrophy, LV remodeling and volume increases in adults with hypertension in rural Chinese population. The prevalence of LVH was statistically different among three groups and the rates of LVH were higher when LVM was indexed to heightA, atrial peak flow; AOD, Aortic annular diameter; BMI, Body mass index; BP, Blood pressure; BSA, Body surface area; CVD, Cardiovascular disease; DBP, Diastolic blood pressure; E, Early transmitral diastolic peak flow; FPG, Fasting plasma glucose; HDL-C, High-density lipoprotein cholesterol; IVSd, Interventricular septal thickness; LAD, Left atrial diameter; LDL-C, Low-density lipoprotein cholesterol; LV, Left ventricular; LVEDV, LV end-diastolic volume; LVESV, LV end-systolic volume; LVH, Left ventricular hypertrophy; LVIDd, LV end-diastolic internal dimensionn LVIDs; LV end-systolic internal dimension; LVM, Left ventricular mass; LVMI, Left ventricular mass index; MAP, Mean artery pressure; PC, Plasma creatine; PP, Pulse pressure; PWTd, Posterior wall thickness; RWT, Relative wall thickness; SBP, Systolic blood pressure; TC, Total cholesterol; TG, Triglyceride; WC, Waist circumference.


Patients with sickle cell disease have significant morbidity and mortality. Pulmonary hypertension is suggested to be an important contributor but its nature and severity in these patients and how best to non-invasively assess it are controversial. We hypothesised that a high-output state rather than primary pulmonary vascular pathology may be the major abnormality in sickle cell disease. This study aimed to evaluate the characteristics and severity of pulmonary hypertension in patients with sickle cell disease using detailed echocardiography.-1 but only 2% had elevated pulmonary vascular resistance and the prevalence of right ventricular dysfunction was very low. Patients with raised tricuspid regurgitant velocity had significantly elevated biventricular volumes and globular left ventricular remodelling, related primarily to anaemia. In a subgroup of patients who underwent cardiac catheterization, invasive pulmonary haemodynamics confirmed the echocardiographic findings.We undertook a prospective study in 122 consecutive stable outpatients with sickle cell disease and 30 age, gender and ethnicity-matched healthy controls. Echocardiographic evaluation included 3D ventricular volumes, sphericity, tissue Doppler, and non-invasive estimation of pulmonary vascular resistance. 36% of patients had a tricuspid regurgitant velocity ≥2.5 m.sElevated cardiac output and left ventricular volume overload secondary to chronic anaemia may be the dominant factor responsible for abnormal cardiopulmonary haemodynamics in patients with sickle cell disease. 3D echocardiography with non-invasive estimation of pulmonary vascular resistance represents a valuable approach for initial evaluation of cardiopulmonary haemodynamics in sickle cell disease. Sickle cell disease (SCD), prevalent in peoples of African descent, results from the presence of haemoglobin S (HbS) due to a genetic mutation in the β-globin chain of haemoglobin. The abnormal HbS polymerizes under low oxygen conditions leading to the formation of irreversibly sickled red blood cells that cause repeated episodes of vaso-occlusion and chronic anaemia, with multi-organ complications that impose substantial morbidity and reduce life expectancy . With im-1 as a surrogate marker of abnormally elevated pulmonary arterial pressure and reported that >30% of patients had abnormal values and that this correlated with an increased likelihood of premature death [-1 in SCD [Considerable attention has focused on pulmonary arterial hypertension as a potential cause of long-term morbidity and mortality in SCD –6. It ware death . Other s1 in SCD ,8. Howev1 in SCD ,10. More1 in SCD ,11. In t1 in SCD  found onMost screening studies in SCD to date have employed basic 2D Doppler echocardiography and have not taken advantage of techniques such as 3D imaging , tissue Doppler, strain analysis and non-invasive estimation of pulmonary vascular resistance (PVR). Cardiac output in SCD is often significantly elevated secondary to chronic anaemia and may confound interpretation of TRV. We hypothesized that elevated cardiac output rather than an elevated PVR may be the major driver of abnormal cardiopulmonary haemodynamics in SCD and that the relative contributions of these factors can be assessed by comprehensive echocardiography. The primary aim of this study was to prospectively undertake comprehensive non-invasive evaluation of cardiopulmonary haemodynamics in a large population of outpatients with SCD and stable symptoms.We studied 152 subjects, comprising 122 consecutive adult outpatients with stable SCD and 30 healthy controls matched for age, gender and ethnicity. Patients with a painful sickle crisis within the previous 6 weeks were excluded. The SCD genotype was haemoglobin SS in 82 (67%), haemoglobin SC in 22 (18%) and haemoglobin S-beta thalassaemia in 18 (15%). Controls were recruited from the general public and hospital staff. The study complied with the Declaration of Helsinki and was approved by the National Research Ethics Service London Dulwich Committee and the King’s College Hospital Directorate of Research and Development. All participants provided written informed consent.echo) was derived from TRV and the RV outflow tract time-velocity integral , as previously described [Transthoracic echocardiography was performed according to American Society of Echocardiography guidelines , using aescribed . 2D coloescribed . Tricuspescribed . Images LV myocardial strain analysis was performed using standard grayscale 2D images in the short axis parasternal view at the level of the papillary muscle and in the 4-chamber apical view. Myocardial deformation was quantified at basal, mid and apical levels by speckle tracking analysis . Strain Full-volume 3D datasets were obtained from the apical 4-chamber window over 4 consecutive cardiac cycles and analyzed off-line . 3D sphe-1 underwent right heart catheterization, pulmonary high resolution computed tomography, and lung function testing, performed within a 2-week window for each patient. Measurements were made of pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP) and thermodilution cardiac output. Pulmonary vascular resistance (PVRRHC) was calculated in Wood Units. Computed tomography was performed on a dual detector helical scanner . Lung function tests were assessed according to American Thoracic Society/European Thoracic Society guidelines [A random subset of 18 patients with a TRV ≥2.5 m.sidelines .Routine haematology and biochemistry profiles were performed in the local hospital laboratories.Data are presented as mean±SD or percentage as appropriate. Student's t-test was used to compare continuous variables and Chi square or Mann-Whitney U test to compare dichotomous variables. Associations between continuous variables were quantified by Pearson’s correlation coefficients (two-tailed). Multivariable regression models with stepwise elimination, based on a selection of clinical and laboratory variables, were created to determine the independent determinants of echocardiographic parameters. Standardized (beta) coefficients were calculated for covariates in models. Data analyses were performed using SPSS statistical software. P<0.05 was considered significant.All patients and controls were of African-Caribbean or African ethnic origin, with a majority of females. The SCD cohort had typical clinical characteristics of the disease, including multi-organ complications, chronic anaemia, reticulocytosis and mild hypoxaemia . 62% of echo values than control subjects . On multivariable regression analysis, the independent determinants of PVRecho ≥2 Wood units were a history of pulmonary embolism and advancing age.We looked for association between TRV and various clinical, laboratory and echocardiographic parameters and then undertook multivariable regression analysis for independent determinants of TRV ≥2.5 m.s.5 m.s-1 . Since v-1 in patients with SCD is accompanied by increased cardiac volumes, likely due to chronic anaemia, but is rarely related to a raised PVRecho. To confirm this and to establish the contribution of elevated pulmonary venous pressures, we undertook right heart catheterization in 18 SCD patients with TRV ≥2.5 m.s-1. Echocardiography was repeated on the day of catheterization; 2 patients had TRV <2.5 m.s-1 on this occasion. Patient clinical characteristics were similar to the overall group of 44 patients with TRV ≥2.5 m.s-1.The findings so far suggest that elevated TRV ≥2.5 m.s-1 (range 4–12 L.min-1). 8 patients (44%) had PCWP ≥15 mmHg, indicative of pulmonary venous hypertension. 13 patients (72%) had significant parenchymal lung disease on computed tomography, including the 1 patient who met diagnostic criteria for pulmonary arterial hypertension. All 15 patients who had lung function tests showed abnormal results.-1 greatly overestimated PAP and only 1 patient met diagnostic criteria for pulmonary arterial hypertension. echo and invasively measured PVR (PVRRHC). No patient had a PVRRHC >3 Wood units . The 2 patients with PVRRHC between 2–3 Wood units had PVRecho values in the same range and had TRV >4 m.s-1. None of the 16 patients with PVRecho <2 Wood units had a PVRRHC over this value; i.e. no patients with even physiologically elevated PVR were missed by using a conservative PVRecho cut-off of 2 Wood units.-1, there is little evidence of haemodynamically significant pulmonary hypertension as assessed by RV function and non-invasive PVRecho; (b) patients with raised TRV have elevated cardiac output, biventricular dilatation and 3D features of volume overload, likely to be related to chronic anaemia. Therefore, the high-output state of SCD rather than primary abnormalities of the pulmonary microvasculature may be the major driver of abnormal pulmonary haemodynamics. To our knowledge, this is the first prospective study to use comprehensive 2D and 3D echocardiography to evaluate the complex cardiopulmonary physiology of SCD outpatients.The main findings of this study in stable SCD outpatients are that: (a) although >35% of patients have TRV ≥2.5 m.sThe prevalence and role of pulmonary hypertension in the pathophysiology and outcome of SCD are controversial. Reports by Gladwin ,21 and oecho and, furthermore, there was no evidence of significant RV dysfunction as assessed by ejection fraction or TAPSE. In fact, SCD patients with TRV ≥2.5 m.s-1 had more hyperdynamic RV function than those with lower TRV values indicating an absence of RV pressure overload. These findings were confirmed in the subgroup of patients with TRV ≥2.5 m.s-1 who underwent invasive assessment; only 1 patient met the diagnostic criteria for pulmonary arterial hypertension. It should be noted that the thermodilution method may underestimate cardiac output in patients with significant TR and high flow but this would, if anything, result in an overestimation of the PVR.Our study confirms the high prevalence of elevated TRV in unselected SCD outpatients but, consistent with previous work , we find-1 but markers of haemolysis  were not independent predictors, arguing against haemolysis, nitric oxide consumption and consequent increase in PVR as a potential mechanism. Chronic anaemia in SCD is known to be accompanied by an increase in LV volumes and mass [-1. 3D echocardiography not only allowed more accurate estimation of volumes than 2D echocardiography [per se may lead to elevated pressures if PVR is unchanged. Secondly, LV volume overload may lead to elevated pulmonary venous pressures and resistance. We found evidence for both mechanisms in that cardiac index was increased in SCD patients and a high proportion (44%) of those who underwent cardiac catheterization had an elevated PCWP. Taken together, these results strongly suggest that a high-output state per se is the major driver of abnormal pulmonary haemodynamics, both through direct (flow) and indirect (LV overload) mechanisms. The majority of our patients (67%) had the haemoglobin SS genotype, with only 18% haemoglobin SC and 15% haemoglobin S-beta thalassaemia, and so no systematic comparison among genotypes was undertaken. However, the results in the haemoglobin SS group reflected those in the total cohort. The finding in multivariable analyses that haemoglobin concentration was the main independent determinant of both TRV and LVEDV suggests that any difference between genotypes may be related mainly to the haemoglobin concentration and associated severity of high-volume state.We then wished to establish the reasons for elevated TRV values in a high proportion of SCD patients. We found that haemoglobin concentration was an independent determinant of TRV ≥2.5 m.sand mass –23, and iography  but alsoecho) that has been validated in a non-SCD population [echo tended to overestimate PVRRHC, with SCD patients known to often have raised LV filling pressures [RHC >2 Wood units were missed by the use of PVRecho. Therefore, our results suggest that PVRecho may be a useful estimate of PVR in SCD.In this study, we used a non-invasive echocardiography-based estimate of PVR  of abnormal pulmonary haemodynamics are of significant therapeutic relevance. Agents such as endothelin receptor antagonists and phosphodiesterase V inhibitors may be effective in pulmonary arterial hypertension where an increased PVR is the major pathogenic factor . Howeverecho are especially useful in this population. A limitation of our study is that we did not have detailed data on biomarkers (e.g. NT-proBNP) or objective functional capacity in the study population, which would be valuable in the overall evaluation of these patients. In conclusion, this study suggests that a dominant factor that contributes to abnormal pulmonary haemodynamics in stable SCD is the elevated cardiac output and volume overload state associated with chronic anaemia.The evaluation of cardiopulmonary haemodynamics and its contribution to disease pathophysiology and outcome in SCD is complex. Invasive right heart catheterization remains the gold-standard for accurate measurement of pulmonary vascular pressures and resistance, but comprehensive non-invasive evaluation by echocardiography can identify a large proportion of patients in whom such invasive assessment may be unnecessary. Our study indicates that 3D analysis of ventricular volumes and sphericity, cardiac index, analysis of RV function, and estimation of PVRS1 Table(DOCX)Click here for additional data file.S2 TableVariables included in the model were: age, gender, history of pulmonary embolus, haemoglobin concentration, LDH level, proteinuria, and cardiac index.(DOCX)Click here for additional data file.S3 TableTPG, transpulmonary gradient, ILD, interstitial lung disease.(DOCX)Click here for additional data file.