How deceleration capacity (DC) and acceleration capacity (AC) of heart rate associated with atrial fibrillation (AF) and ablation is still not clear. The dynamic changes of AC, DC and conventional heart rate variability (HRV) parameters were characterized in 154 subjects before circumferential pulmonary veins isolation (CPVI) and three days, 3 months and 6 months after CPVI. The DCs of the recurrent group decreased significantly at each time point after CPVI; the DCs of the recurrence-free group before CPVI and three days, 3 months and 6 months after CPVI were 7.06 ± 1.77, 3.79 ± 1.18, 4.22 ± 1.96 and 3.97 ± 0.98 ms respectively, which also decreased significantly at each time point and were significantly lower than these of recurrent group. Conversely, the AC of recurrent and recurrence-free groups increased significantly at each time point after CPVI; the ACs of recurrence-fee group were significantly higher than these of recurrent group at each time point. No stable difference trend of HRV parameters was found between two groups. Further Kaplan–Meier analysis showed that DC < 4.8 ms or AC ≥ −5.1 ms displayed significant higher recurrence-free rates. In conclusion, high AC and low DC imply higher AF-free rate after ablation. Normal autonomic nervous system (ANS) coordination is critical for cardiac function maintaining3. However, disorganized ANS activation can induce atrial fibrillation (AF)4. The overall role of sympathetic nerves in the heart is to modulate the automaticity of sinoatrial node and the conductivity of atrioventricular node3. Abnormal adrenergic activation may promote focal activity of atrial myocytes via enhanced automaticity, early afterdepolarization or delayed afterdepolarization; which may act as a trigger of AF or an AF-maintaining driver3. The general effect of vagal nerve on the heart is to reduce the automaticity of sinoatrial node and the conductivity of atrioventricular node3. Abnormal parasympathetic activation produces spatially heterogeneous action potential and refractory period abbreviation, which may promote the occurrence and maintenance of re-entrant activity3.The heart is richly innervated by the sympathetic and parasympathetic  nerves9. Thus, PV isolation (PVI) rapidly replaced focal ablation and emerged as a main therapeutic strategy to treat AF12. The efficacy and major complications of catheter ablations are now approximately 70–80% and 5% respectively9.Recent basic science concepts and clinical catheter-based AF-ablation techniques showed that most paroxysmal AF is triggered by ectopic firing originating from the cardiomyocyte sleeves extending to the pulmonary vein (PV) and the junction between PV and left atrium9. Current measures of cardiac electrophysiology, including conventional heart rate variability (HRV), are hard to distinguish the respective role of sympathetic and parasympathetic nerves in the cardiac pathophysiology of AF14. In 2006, Baver et al. created a series of signal processing technology and algorithm to separately characterize the deceleration and acceleration capacities of the heart rate using 24-h ambulatory electrocardiogram15. Their calculation principle and later reports suggested that AC and DC might distinguish and quantify between vagal and sympathetic nervous system roles that affect cardiac electrophysiology17.Despite encouraging achievements of catheter ablation in AF therapy, how to improve the long-term efficacy requires further knowledge on how ablation rectified the ANS modulation in cardiac electrophysiologyIn this report, to evaluate whether AC/DC have the potential to discriminate AF recurrence, 154 qualified paroxysmal AF subjects were assembled. The dynamic change trend of AC and DC before and after CPVI was compared between recurrent and recurrence-free subjects.The review board of the First Affiliated Hospital of Soochow University approved this protocol in accordance with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. Written informed consent regarding procedures and medical data were obtained from all of the patients according to the guidelines of the Chinese National Ethics Regulation Committee. All patients were informed of their rights to withdraw consent personally or via kin, caretakers, or guardians.3. Drug-resistant paroxysmal AF was defined at least 2 ineffective antiarrhythmic drugs in suppressing AF recurrence3.All subjects involved in this study were drug-resistant paroxysmal AF patients. Paroxysmal AF is defined as an episode of AF that terminates spontaneously or with intervention within 7 days of onset or episodes may recur with variable frequencyInitially, 219 patients with paroxysmal AF were treated with radiofrequency ablation in our Department of Cardiology from January 2013 to November 2015 . 24 hours before CPVI, transesophageal echocardiography was performed to exclude the possibility of thrombus in left atrial appendage and left atrium, the anatomical structures of the left atrium and pulmonary vein were determined by CT scan. Patients with a previous catheter ablation; coronary insufficiency; recent myocardial infarction; clinical symptoms of heart failure; relevant valvular dysfunction; terminal renal insufficiency, obstructive sleep apnea, chronic obstructive pulmonary disease or any other relevant pulmonary disease; hyperthyroidism/hypothyroidism; inflammatory diseases; diabetes and sick sinus syndrome were excluded from this study.Under the guidance of three-dimensional mapping system , CPVI was performed using cold saline perfusion . Under local anesthesia; puncture the left femoral vein; insert 10 polar sinus electrodes to the distal coronary vein and fix with skin paste; puncture the right femoral vein twice; insert the Agilis and SL1 long sheaths  respectively. The puncture needle  is sent to the atrial septum via the SL1 long sheath; SL1 long sheath are sent into the left atrium after piercing atrial septum. The electrodes of saline infusion radiofrequency catheter ablation are sent to left atrium via the Agilis long sheath. Under the positioning of the EnsiteNavx , complete the following procedures: construction of the three-dimensional model of left atrium; mapping the potentials of the left superior, left inferior, right superior and right inferior pulmonary veins; determination of pulmonary vein orifice and left atrial appendage position; setting the circumferential pulmonary vein ablation line; loading the electrodes of saline infusion radiofrequency catheter ablation; the left and right pulmonary vein macrocyclic isolation along the ablation line. Dormant conduction was assessed by isoproterenol infusion, pulmonary vein pacing, coronary vein and intra atrial pacing.All patients received postoperative dabigatran  for anticoagulation; amiodarone  to maintain sinus rhythm; and omeprazole  to suppress gastric acid for 3 months. Patients with discomfort will be submitted for the ECG monitoring. The cardiac electrophysiology and echocardiography of all patients will be evaluated using 24-h ambulatory electrocardiograms and a Sonos 5500 type ultrasound machine  three days, 3 months and 6 months after operation to learn the efficacy and complications of CPVI.3. According to the “2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation”, the recurrence of AF within 3 months was defined as early recurrence3. In this study, the average time of the third time point (3 months after CPVI) was 90 ± 5 days, so, paroxysmal atrial arrhythmias; such as atrial tachycardia, atrial flutter and AF lasting more than 30 seconds detected at this time point was defined as early recurrence. AF recurrence > 30 s recorded at the fourth time point (6 months after CPVI) was defined as late recurrence.The time point to define postoperative recurrence of AF has not yet unified. Three months after radiofrequency ablation is a blank periodTo monitor the cardiac electrophysiology of all participates before and after ablation, a Holter monitor test was performed using a Holter Monitoring DigiTrak XT Holter System .17 to the RR interval series, which is capable of detecting and quantifying quasi-periodic oscillations masked by nonperiodic components, artifacts and ectopic beats, was adopted in analysis of 24-h ambulatory electrocardiograms. The DC and AC were computed with timescales (T) = 1 and wavelet scales (s) = 2. To avoid errors caused by artifacts and ectopic rhythm; abnormal RR intervals, defined as RR intervals that change by more than 20% from the previous RR interval, were removed automatically; sinus arrhythmia and ventricular rhythm were further excluded manually according to the P waves morphology and QRS waves shape respectively.A phase-rectified signal averaging (PRSA) algorithmBriefly, step 1, Definition of decelerating and accelerating anchors: heartbeat intervals longer than the preceding interval were identified as decelerating anchors; heartbeat intervals shorter than the preceding interval were identified as accelerating anchors. Step 2, definition of cardiac electrical segments: segments of interval data around the decelerating and accelerating anchors are selected. Step 3, phase rectification: the cardiac electrical segments described above were aligned at the decelerating and accelerating anchors. Step 4, signal averaging: the phase-rectified signal averaging signal X(i) was obtained by averaging the signals within the aligned cardiac electrical segments. Step 5, quantification of deceleration and acceleration capacities using the following formula: DC (AC) = [X(0) + X(1) − X(−1) − X(−2)]/4.14, the HRV parameters were computed using same set of 24 h ambulatory electrocardiograms while calculating AC and DC. The quality control of the RR interval series was performed as AC/DC computation, that is, abnormal RR intervals, defined as RR intervals that change by more than 20% from the previous RR interval, were removed automatically; sinus arrhythmia and ventricular rhythm were further excluded manually according to the P waves morphology and QRS waves shape respectively. Indices of time-domain methods include the full-course standard deviation of NN  intervals (SDNN); root mean square of successive differences ; indices of frequency-domain methods, which assign bands of frequency and then count the number of NN intervals that match each band, these include high frequency (HF), low frequency (LF) and the LF/HF; and average heart rate; were computed using Kubios HRV analysis software (http://kubios.uef.fi).According to the guidelines: Heart rate variability, Standards of measurement, physiological interpretation, and clinical use16, a transthoracic echocardiographic examination was performed using a Sonos 5500 type Ultrasound machine  with a 2.5 Hz transducer. The parameters measured with the M-mode technique included left ventricular end-diastolic, end-systolic and left atrial diameters. The measurement of the left ventricular ejection fraction was performed using the Simpson’s biplane method.As previously describedAll of the echocardiographic and above cardiac electrophysiological examinations were performed and analyzed licensed technicians who were blinded to clinical data and group division.Continuous variables are presented as means ± standard deviation (SD); a non-paired Student’s t-test were used for comparison between groups. Categorical data are summarized as frequencies and percentages and compared using chi-square test and/or Fisher’s exact test. Kaplan–Meier analyses with log-rank tests were used to calculate AF recurrence-free survival over time and compare recurrence rates between groups. The performance of discrimination was evaluated by an area under receiver operating characteristic (ROC) curve (AUC). P values less than 0.05 (two-sided) were deemed statistically significant. Statistical analyses were performed using SPSS version 17.0 .219 patients with drug refractory paroxysmal AF were collected initially from January 2013 to November 2015. Of whom, 16, 5, 2, 5, 12, 5, 10, 4 and 6 individuals were excluded from this reports due to typical atrial flutter, refusing ablation, incomplete CPVI due to pericardial tamponade, tricuspid isthmus ablation, left atrial linear ablation, complication of atrial tachycardia, superior vena cava isolation, ablation of left-sided atrioventricular accessory pathways and lost to follow-up, respectively. Finally, 154 qualified patients with paroxysmal AF were involved in this study  curve was plotted using AC and DC values of each patient. The area under ROC curve (AUC) of AC and DC were 0.747 (95% CI 0.618 to 0.875) and 0.758 (95% CI 0.630to 0.886) respectively. As expected, AC and DC displayed good performance to discriminate recurrence-free subjects. The pointcuts of AC and DC were −5.1 and 4.8 ms respectively.Next, the recurrence-free rates were analyzed using above cut off values. During 6 months of follow-up, 34 (22.1%) and 54 (35.1%) of the 154 patients showed AF recurrence within 3 and 6 months following up, respectively. Kaplan–Meier analysis according to DC  and wavelet scales (s) used in the computation20. Either DC or AC was solely dependent on vagal activity under the scales of T = 1 and s = 2; however, with the scales of T = 3 and s = 5, both DC and AC were correlated positively to sympathetic activity and negatively to vagal activity. In our study, the DC and AC were computed with T = 1 and s = 2. If the above theory is adopted to interpret our results, high DC and low AC might predict more severe disorders of vagal modulation in heart eletroneurophysiology and then easily cause early AF recurrence.A recent study using a cardiovascular system model showed that the eletroneurophysiological properties of DC and AC were highly influenced by the timescales  was higher than above normal Chinese with similar age. This difference may also be explained by that AF associated with higher vagal tension19.Our data showed that all the SDNN, RMSSD and LF/HF of recurrence-free and recurrence groups displayed a separation and coincidence tendency after the ablation, which might reflect the injury and repair of PV after ablation. Nevertheless, no stable tendency of the HRV parameters was found. A study examining 636 Chinese subjects without heart disease showed that DC, SDNN, RMSSD varied by age, gender and circadian rhythm23 propafenone slows the influx of sodium ions into the cardiac muscle cells, causing a decrease in excitability of the cells;24 and metoprolol blocks β1 adrenergic receptors in heart muscle cells, thereby decreasing the slope of phase 4 in the nodal action potential and prolonging repolarization of phase 325. In general, these medicines are mainly to control arrhythmia by affecting the action potential of cardiac myocytes. DC and AC are derived from the heartbeat intervals. Thus, amiodarone, propafenone and metoprolol administration should have limited effect on AC and DC. Be the evidence, our data showed that none of the three medicines changed the HRV indexes or AC and DC significantly, which is also consistent with other reports partially27.In our report, 85 (55.2%), 26 (16.9%) and 74 (48.1%) subjects were treated with amiodarone,propafenone and metoprolol, respectively. As we know, amiodarone slows conduction rate and prolongs the refractory period of the SA and AV nodes;et al. applied the PRSA algorithm in AC and DC of the heart rate17, more and more studies have found that AC and DC are related not only to physiological activity but also to a number of pathophysiological states. DC decreased gradually with age increase in normal population;22 the magnitudes of DC and AC increased progressively as breathing frequency decreased;28 lower DC of heart rate is a strong and independent predictor of 1-year mortality in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation;29 AC is positively associated with heart failure grade in patients with dilated cardiomyopathy;16 lower DC assessed from short-term recordings is a strong and independent predictor of mortality and cardiovascular mortality after myocardial infarction30. These reports showed the complex role of ANS in the physiological and pathological process. More extensive and deeper researches are needed to figure out the overview of ANS.Since Kantelhardt JW T = 1 and s = 2 only, we had not computed the AC/DC using other scales.There are several limitations in our study, firstly, we had only followed up the patients for only 6 months, we will continue to observe these patients and will provide long-term data in our next study; secondly; we computed the AC and DC under scales


Percutaneous vertebroplasty procedure is of major importance, given the significantly increasing aging population and the higher number of orthopedic procedures related to vertebral compression fractures. Vertebroplasty is a complex technique involving the injection of polymethylmethacrylate (PMMA) into the compressed vertebral body for mechanical stabilization of the fracture. Our understanding and ability to modify these mechanisms through alterations in cement material is rapidly evolving. However, the rate of cardiac complications secondary to PMMA injection and subsequent cement leakage has increased with time. The following review considers the main effects of PMMA bone cement on the heart, and the extent of influence of the materials on cardiac embolism. Clinically, cement leakage results in life-threatening cardiac injury. The convolution of this outcome through an appropriate balance of complex material properties is highlighted via clinical case reports. Approximately 700,000 people suffer from vertebral compression fractures in the United States, costing over $1 billion for treatment and management . PVP wasPMMA is an inert material which is not reabsorbed in the human body. The polymer achieves 90% of its ultimate strength within one hour of injection . AlthougThis review will focus on the mechanisms present at the bone cement interface, related cardiovascular changes in particular, the intra-cardiac embolism, and the various alternatives and solutions that have been described. The paper will also give the reader an idea about important publications on bone cement polymer related cardiac emboli.One of the significant complications in the reinforcement of vertebral compression fracture is cement leakage, which flows to the cardiac region . Here we describe various factors that play a role in cement leakage to the heart. Among all the factors, PMMA viscosity is probably one of the most important determinants dictating cardiac embolism. In addition, advances in mathematical models related to PMMA cement have been discussed in detail.Several factors related to cement leakage include: bone permeability, marrow viscosity, bone porosity, size of the injection cavity, diameter of the leakage path, bone pore size, and cement viscosity . Among tThe use of high-viscosity cement seems to stabilize cement flow. However, the forces required for the high-viscosity cement delivery are significantly higher and may approach or even exceed the human physical limit of injection forces. Higher injection forces may also result in poor filing of the cement . AnotherViscosity is probably the most important material property responsible for cement leakage. An ideal bone cement, when injected, should stabilize vertebral compression fractures. An increase in the viscosity of PMMA cement is associated with a fast polymerization process. This actively relates with a higher released temperature and a shorter setting time  21]. Ad. Ad21]. Hydrogen peroxide, used as hemostatic agent in arthroplasty, has been shown to adversely affect the material properties of PMMA . Propertη is the viscosity, γ is the shear rate, st and sγ are the characteristic time and shear rates, respectively, and a, b, c, d are the viscosity material parameters. This rheological model of PMMA bone cements was implemented in ANSYS (Finite Element package) and the agreement between the analytical and numerical solutions confirmed that the proposed model appropriately captured both the rheopectic and pseudoplastic behaviors [The rheological properties are important factors influencing the cement flows and they may play a part in the formation of the pores in the cement during polymerization. These pores are postulated to act as sites for the initiation of cracks which contribute to the aseptic loosening of the prosthesis . During ehaviors . The fineD is the diameter of the path of least resistance, p is a dimensionless parameter of the matrix porosity, K is the matrix permeability, cμ is the cement viscosity, mμ is the marrow viscosity, R0 is the radius of the cavity at the injection point, eL is the length of the path of least resistance, and f is a function of the parameters within the brackets. Extravasation occurs when the risk factor is larger than 1.A theoretical model was proposed by Bohner et al. to analyze the distribution of a PMMA cement after its injection into a porous structure . The calR1 and R2 at its ends can be derived as [Q is the flow rate, μ is the dynamic viscosity of PMMA, R is the cannula radius, and L is the cannula length.In order to account for the non-Newtonian nature of curing PMMA in a simulation of PMMA injected through a cannula to improve quantitative accuracy, Lian et al. developed a biochemical model for PMMA injection by approximating the cancellous bone trabecular network as a branching-pipe network . The overived as :(3)−ΔP=This computational model approach demonstrated the potential of simulating PMMA injection into cancellous bone during percutaneous vertebroplasty. This model employed the Hagen–Poiseuille law to predict the pressure drop across a delivery cannula with viscoelastic changes of curing PMMA modeled via a time and shear-rate dependent power law. The power law that was derived based on dynamic rheological testing of curing PMMA samples was fitted with experimental data. In conjunction with a branching-pipe geometrical model, the method helped with quick estimation of the overall injection pressure, and, hence, the reaction force during manual PMMA injection . For reaIntra-cardiac embolism (ICE) secondary to PMMA leakage could be an incidental finding or it may appear during the procedure, immediately following the procedure, during hospital recovery, or even manifest as a long term complication (ranging from days to years) (Adding hydroxyapatite (HA) to PMMA cement to reduce the quantity of barium, which is used as a radiopacifier, may aggravate cardiovascular deterioration in the event of cement embolism by the activation of coagulation. Acute cardiovascular consequences of considerable PMMA leaks (2 mL) may not be severe in persons with a healthy cardiopulmonary system. Subsequent addition of hydroxyapatite (10%) to PMMA cement did not result in more severe cardiovascular changes . It is pOver time, many varieties of injectable materials have been proposed for use in order to reduce cement leakages . CalciumMeanwhile, vertebroplasty with CP yields better clinical and radiological results than conservative treatments for primary vertebral fractures, with the exception of some intraoperative complications, such as leakage and embolism . AnotherHydroxyapatite (HA) has been explored as an alternative. The properties of bone conductivity and the absence of exotherm of hydroxyapatite-forming materials make them an attractive alternative to PMMA cements . Thus, wProper opacification is essential for fluoroscopic monitoring of cement injection to prevent extravasation and, thus, the potential complication of pulmonary embolism ,60. The There are adverse effects on injectability, viscosity profile, setting time, mechanical properties of the cement, and bone resorption. Altogether, radio-opacifiers are considered to be beneficial depending on their type and concentration. In order to overcome these issues, PMMA microspheres in which gold particles are embedded and its monomer is the same as that used in commercial cements for vertebroplasty have been attempted .Orthocomp™ is composite material with a matrix of Bis-phenol glycidyl dimethacrylate (BisGMA), Bis-phenol ethoxy dimethacrylate (BisEMA), and triethyleneglycol dimethacrylate (TEGDMA) . It is bVarious optimization tools have also been utilized. The impact of the injection device and viscometer in controlling cement leakage has been suggested. Gisep’s study showed a strong correlation of the PMMA viscosity during setting to the injection forces through vertebroplasty injection devices ,68. TherThe drug delivery system releasing Vancomycin, an antibiotic, from bone cement is controlled according to Higuchi’s theory. Imperfect polymerization of the polymer could cause the monomer to leak and therefore change the matrix structure. Hence, it could affect the release of antibiotics from bone cement beads. One must prepare cement beads properly, taking into consideration Higuchi’s equation in order to control release by adjusting the amount of drug in the beads and the diameter of the cement device .The particle release of porous PMMA cements during curing has been studied, because the release of powder ingredients obtained from porous PMMA can theoretically cause negative effects such as embolism. The invention of porous PMMA, in order to make regular PMMA cement more compliant with cancellous bone, while initially promising, remains questionable . The risPMMA cement cardiac embolism is a potentially serious complication following vertebroplasty and kyphoplasty. The frequency of pulmonary cement emboli following percutaneous vertebroplasty varies from 4.6% to 26.9% ,73,74,75A 61-year-old woman with a history of ovarian carcinoma on chemotherapy and vertebral osteoporotic compression fractures presented with acute onset shortness of breath. She was undergoing evaluation for prolonged back pain. Magnetic resonance imaging (MRI) showed compression fractures at the T11, L1, and L2 vertebrae with no significant retropulsion. In view of her persistent pain and the failure of conservative management, she underwent vertebroplasty of the T11, L1, and L2 vertebrae using PMMA cement mixed with barium at an outside hospital. There was a small amount of cement extravasation into the paraspinal veins and prevertebral veins that was noted during the procedure.Eight hours after the procedure, the patient complained of shortness of breath. She was intubated due to profound hypoxia. Chest X-ray and a Computed Tomography (CT) thorax scan showed multiple dense pulmonary radio-densities along with the presence of cardiac radio-densities . TransthThe frequency of ICE remains unknown. Only a few isolated case reports exist in the literature. ICE is attributed to the passage of the leaked PMMA from the perivertebral veins into the azygos vein and then onwards to the inferior vena cava and finally to the right cardiac chambers . In caseSome authors have reported the use of a preinjection venogram to decrease the incidence of pulmonary embolism, and the injection of sclerosing agents into the vertebral body before vertebroplasty has also been suggested to close venous channels ,75,76. LThe treatment for symptomatic ICE is surgical retrieval. It is extremely useful if the bone cement is densely adhered to the adjoining cardiac wall or if it is free floating in the pericardial space ,31. In tIn select cases, percutaneous removal by snare catheter and/or trapping of the embolic fragments by Greenfield filter  (especiaIn this paper, we have reviewed the aspects of PMMA material properties that are relevant to orthopedic and cardiovascular applications. It is important to note that cement leakage is asymptomatic in most situations. PMMA viscosity regulated by density and particle size is one of the important determinants in the formation of the cardiac emboli that may have life threatening implications. Additionally, avoiding excessive PMMA injection and excessive pressure during injection may play a role in prevention . RecentlHowever, despite large investments into engineering research, developments remain limited mostly as a result of the lack of availability of the perfect candidate for bone cement. Long term complications can be devastating due to PMMA presence in the coronary arteries or in the chambers of the heart. The careful evaluation and search for the ideal bone cement systems and methods is crucial for important orthopedic procedures such as vertebroplasty and kyphoplasties.


Cardiac magnetic resonance feature tracking (CMR-FT) was used for LV longitudinal-, circumferential-, and rotational deformation indices. Global systolic LV function was preserved in CoA patients  when compared to controls, with normal LV dimensions and mass (p > 0.05). Twelve CoA patients (55%) were hypertensive, of whom 4 were on anti-hypertensive medication. LV global longitudinal strain was preserved in the four-chamber  and two-chamber  orientations in CoA patients. Global circumferential strain was preserved at basal , mid-ventricular , and apical levels . No differences were found in global torsion , twist , and recoil rate . Analysis of intra-observer variability demonstrated good reproducibility for all CMR deformation indices. Global and rotational myocardial deformation indices are preserved in CoA patients long-term after repair without residual stenosis, despite a high incidence of hypertension.Arterial vasculopathy and residual aortic obstruction can lead to left ventricular (LV) dysfunction in patients with coarctation of the aorta (CoA) related to adverse ventriculo-arterial coupling. This study aimed to investigate potential differences in LV myocardial deformation indices between repaired CoA patients and healthy controls. Twenty-two CoA patients (age 30 ± 10.6 years) after surgical repair ( Coarctation of the aorta (CoA) is defined as a localized narrowing of the aorta, which can be repaired through endovascular and/or surgical treatment , 2. DespPrevious studies have demonstrated preserved or even increased global cardiac function, e.g., LV ejection fraction (LVEF), in patients treated for CoA , 11. HowThe study population consisted of 22 patients who were successfully treated for CoA  with surgery or balloon angioplasty (BA) and had a follow-up of at least 10 years. Patients who underwent primary repair of localized membranous CoA between 3 months and 16 years of age between 1969 and 2004 in our institution were included in the study. To allow for comparison between surgery and BA, CoA patients with primary repair before 3 months of age were not included as surgical repair was routine for those patients. Patients with isthmus hypoplasia, aortic arch hypoplasia, and/or severe associated heart defects  were excluded. Twenty-two of the 72 included patients agreed to undergo CMR testing (inclusion rate: 31%). Controls were recruited from a local cohort of healthy volunteers and were age- and gender matched to the CoA patient group.CMR imaging was performed on a 1.5 T scanner . Cine images were obtained using a electrocardiogram-gated breath-hold balanced fast-field echo sequence (SSFP) in long-axis planes (two- and four-chamber views) and short-axis slices covering the LV from the annulus of the mitral valve to the LV apex. Results for cardiac dimensions and LVEF were derived from short-axis slices according to the Society for Cardiovascular Magnetic Resonance recommendations . End-diaCardiac magnetic resonance feature-tracking analysis was performed using feature-tracking software , based on tissue voxel motion tracking to analyze mechanical deformation . InitialLongitudinal strain, strain rate, velocity, and displacement were measured in two- and four-chamber long-axis views Fig. . CircumfMyocardial deformation was analyzed in 16 myocardial segments, in accordance with the American Heart Association’s standardized myocardial segmentation . If adeqRotation was calculated in systole and diastole for the basal and apical slices, by averaging the rotation for all segments in the respective slice relative to the LV center axis. Positive rotation is considered counterclockwise when viewed from caudal to cranial position . Torsiont tests and one-way analysis of variance. Multiple regression was used to assess correlations between different cardiac variables and deformation indices. Intra-observer variability was assessed using the intraclass correlation coefficient (ICC). Data analyses were performed using SPSS, version 22 . A p value < 0.05 was considered statistically significant.Data are expressed as mean ± standard deviation. Statistical comparisons of longitudinal-, and circumferential strain and strain rates, torsion and recoil rates between the CoA group, subgroups and normal controls were performed using unpaired Student’s p < 0.01), with a longer follow-up to CMR , as BA is a more recently introduced technique in our practice. Systolic-, diastolic-, and mean arterial blood pressures  were 135 ± 13.2, 76   ±  8.5, and 96 ± 8.8 mmHg, respectively, for CoA patients. Twelve CoA patients (55%) were hypertensive according to the European Society of Hypertension Guidelines (SBP ≥ 95th percentile) [R2 = 0.78, p = 0.046). No significant correlation was found between LV mass and age, blood pressures, time between repair and CMR, the repair to reintervention interval, or the reintervention to CMR interval . Systolic blood pressure was not significantly correlated with age, BSA, LV mass, intervention to CMR interval, age at time of repair, repair to reintervention interval, or reintervention to CMR interval .The study population consisted of 22 CoA patients and 22 healthy controls. Baseline characteristics of the study population are presented in Table centile) ) at the p = 0.56) . No significant difference in LVEF was found between patients treated for re-CoA and patients without re-CoA .All CoA patients had preserved global systolic LV function when compared to controls  Table . LV massp = 0.06 and p = 0.22, respectively). Global circumferential strain was also preserved at basal (p = 0.43), mid-ventricular (p = 0.09), and apical levels (p = 0.32). Global longitudinal strain rate was increased in CoA patients when compared to controls . Global torsion (p = 0.28), twist (p = 0.34), and recoil rate (p = 0.97) demonstrated no differences between CoA patients and controls .LV global longitudinal strain in the four-chamber and two-chamber planes was similar between CoA patients and controls , and global circumferential strain was significantly correlated with LVEF at the mid-ventricular and apical levels . Basal circumferential strain showed a significant correlation with age at the time of repair . None of the studied LV myocardial deformation indices correlated with SBP, DPB, and MAP .Global longitudinal strain was significantly correlated with LVEF (p < 0.01) and showed a slightly higher LVEF  when compared to CoA patients treated with surgery. Two surgical patients had an LVEF below 55% , versus one BA patient (54%). No CoA patient had an LVEF < 40%. Global strain and rotational indices between the two patient groups were comparable (p > 0.05), despite a slightly decreased apical circumferential strain rate in surgical CoA patients . No significant differences in SBP , DBP , and MAP  were found between surgical and BA patients.Patients treated with BA were significantly younger at time of investigation  and a similar LV mass to LVEDV ratio . No significant differences were found for LVEF (p = 0.83) or LV dimensions . Hypertensive CoA patients demonstrated a slightly increased global longitudinal strain in the four-chamber plane when compared to normotensive patients and controls , but this difference was not statistically significant (Table Hypertensive CoA patients (with SBP ≥ 95th percentile according to the European Society of Hypertension Guideline ) demonstCMR-FT demonstrated good intra-observer reproducibility, with an intraclass correlation coefficient > 0.8 for all global strain, strain rate, and rotational indices. All ICCs are presented in Table Repaired CoA patients demonstrate an increased susceptibility for cardiovascular morbidity and mortality at long-term follow-up , 25–27. global LV systolic function is generally normal;global and regional myocardial deformation indices are preserved in well-repaired CoA patients, despite a high incidence of hypertension;the choice for treatment modality—surgery versus BA—has no impact on LV systolic function or LV myocardial deformation.Global LV function was preserved in our cohort of well-repaired CoA patients at long-term follow-up as previously described, expressed by normal LVEF , 12, 26.Myocardial deformation was preserved in our CoA patients when compared to healthy controls, in agreement with previous echocardiography and CMR-FT reports indicating preserved longitudinal and circumferential strain in CoA patients with preserved global LV systolic function and normal LV mass , 11. JasSurprisingly, our CoA patients demonstrated increased systolic global longitudinal strain rate when compared to our control group. Systolic strain rate has been identified as a strong indicator for LV contractility. Increased contractile performance has been described in CoA patients after repair, as CoA patients experience increased afterload which may lead to myocardial remodeling and LV hypertrophy to maintain normal LV wall stress levels . KimballConflicting data on myocardial deformation after CoA repair may be explained by differences in age at the time of repair, associated severity of CoA, and duration of follow-up between studies. The myocardial response to increased pressure load is age-dependent as the myocardium has the ability to regenerate and increase vascularity in children, thereby restoring pressure-induced remodeling with preservation of coronary blood flow and reduction of development of myocardial fibrosis , 30. DelJashari et al. reported more impaired longitudinal strain in CoA patients with LV hypertrophy, as confirmed by other studies , 28, 31.No difference in myocardial deformation was observed between CoA patients after BA and surgery in our study. Patients after surgery had slightly lower LVEF compared to BA patients, possibly due to the older age of the surgical patients. Similar results have been described by Chui et al. who showed a minor—non-significant—difference in LVEF between both treatment groups .Hypertension is a well-described long-term complication of CoA , 22, 36.A few limitations should be addressed regarding this study. The relatively small sample size limits the generalizability of the results and may have obscured further differences and associations. Our CoA patients were not analyzed for arterial stiffness, so direct assessment of ventriculo–arterial coupling could not be performed. Nevertheless, this study provides insight in myocardial deformation in CoA patients at long-term follow-up, suggesting good LV function in well-repaired patients. The long-term implications of our findings need to be substantiated with follow-up studies.Feature tracking by CMR provides easily accessible and reproducible analysis of myocardial deformation. Well-repaired CoA patients show preserved cardiac function by normal LV ejection fraction and normal myocardial deformation indices at long-term follow-up, despite a high incidence of hypertension. We found good reproducibility for strain, strain rate, and rotational indices with CMR-FT, suggesting CMR-FT is a useful tool for analysis of myocardial deformation.


Background. Surgical correction of mitral regurgitation (MR) can lead to postoperative low cardiac output state. We aimed to assess the acute hemodynamic changes after percutaneous MitraClip therapy  in patients with functional MR without the influence of general anaesthesia. Methods. We studied invasive hemodynamic parameters in 23 patients before procedure , during procedure (intubated patients), and the first day after MitraClip implantation . Results. Mitral valve clipping significantly increased cardiac index (CI) . Conversely, there was significant reduction in the mean pulmonary capillary wedge pressure (PCWP) , mean pulmonary artery pressure , and pulmonary vascular resistance index . Conclusions. The functional MR therapy with percutaneous MitraClip device results in significant increase in CI (+66%) and concomitant decrease in PCWP (−42%). None of our patients developed low cardiac output state. Our results support the idea that significant part of low cardiac output state after cardiac surgery is due to surgery related factors rather than due to increase in afterload after MR elimination. Cardiac surgery for mitral regurgitation (MR)  has a well described risk of deterioration of left ventricular (LV) function and acute postoperative low cardiac output (CO) state, especially in patients with preexisting LV dysfunction. The main known causes of low CO state are elimination of MR with resulting sudden increase in afterload but also several factors inherently linked to the injury due to cardiac surgery—depression of myocardial contractility after cardioplegic arrest, use of cardiopulmonary bypass, and interruption of annular-chordal-papillary muscle continuity. The principal mechanism leading to a decrease in LV systolic function after surgical correction of mitral regurgitation is considered to be the increase in afterload due to elimination of the low-impedance regurgitant flow into the left atrium –3.Percutaneous mitral valve repair with MitraClip device provides a unique model to assess the acute hemodynamic changes solely attributable to elimination of mitral regurgitation. To date, we have limited data on acute hemodynamic changes after MitraClip measured by cardiac catheterisation methods. All previous published reports have significant limitations due to the fact that the measurements of CO before and after MitraClip implantation were performed under general anaesthesia and the studied cohorts were heterogeneous as it included patients with both organic and functional MR –6.We therefore aimed to assess the acute hemodynamic effect after MitraClip therapy in patients with functional MR only and to assess invasively cardiac output state in a “real-world” situation without the influence of general anaesthesia.Our study included 23 consecutive patients with functional MR indicated for MitraClip therapy according to current guidelines; all patients were discussed at the Heart Team meeting. In brief, patients were selected for percutaneous mitral repair if they had moderate to severe (3+) or severe (4+) MR and were symptomatic despite optimal medical therapy, including cardiac resynchronization therapy (CRT) if indicated, were judged inoperable or at high surgical risk and they fulfilled standard echocardiographic morphology criteria predicting procedural feasibility . All patThe procedure was performed under general anaesthesia using transoesophageal echocardiography guidance and fluoroscopy. The MitraClip device  was advanced following an echo-guided transseptal approach to the left atrium and across the mitral valve to the left ventricle. The leaflets were grasped by pullback and arms of the clip were closed. The reduction of MR severity was assessed by Doppler echocardiography. A second clip was placed if further reduction of MR was needed. Acute procedural success was defined as successful clip implantation with MR reduction to grade 2+ or less by echocardiography.T1: a conscious nonanaesthetized patient immediately before the operationT2: 15 min after induction into the general anaesthesiaT3: after clipping at the end of procedure still under GAT4: day 1 after procedure in fully conscious patientHemodynamic parameters were obtained using an arterial catheter , a balloon-tipped Swan-Ganz pulmonary artery catheter, and central venous catheter. Pulmonary capillary wedge pressure (PCWP) was assessed at end expiration and transducers were balanced by determining zero level at the midaxillary line. The Vigilance II Monitor  was used to calculate cardiac output using thermodilution principle and an average of six measurements was used. Systemic (SVRI) and pulmonary (PVRI) vascular resistance indexes and left (LVSWI) and right (RVSWI) ventricular stroke work indexes were calculated according to standard equations.The hemodynamic measurements were performed in 4 exactly defined time points:Clinical follow-up including assessment of New York Heart Association (NYHA) functional status and echocardiography was obtained at 1 month after procedure in all included patients.t-test was used for comparison of LV ejection fraction at baseline and 1-month follow-up. The level of statistical significance was set at p < 0.05. Statistical analysis was computed using software SPSS 23.0.0.0 .Standard descriptive statistics were applied in the analysis: absolute and relative frequencies for categorical variables and mean supplemented by standard deviation for continuous variables. Wilcoxon paired test and Wilcoxon signed-rank test were used for the evaluation of statistical significance of differences between hemodynamic measurements at different time points. Paired The study analysed hemodynamic data from 23 consecutive patients who underwent MitraClip procedure in our centre. Baseline characteristics are summarized in Procedure-related and clinical follow-up data are presented in 2 one day after procedure, p < 0.01). Similarly, MitraClip implantation significantly increased LVSWI  and RVSWI . Conversely, there was significant reduction in the mean PCWP , mean PAP , and mean arterial pressure  and simultaneously reduction in calculated SVRI  and PVRI . Percentage changes in hemodynamic parameters before procedure (T1) and next day after procedure (T4) are shown in Invasive hemodynamic data in the monitored time points are shown in n = 13, defined as CI < 2.5 and PCWP > 15 mmHg before procedure) and the rest of the patients. The similar trend in the increase of CI and the decrease of PCWP, SVRI, PVRI, and mean pulmonary and systemic pressures was maintained also in the group of severe hemodynamically decompensated patients.p = 0.018).Follow-up data were obtained in all included patients. Mitral regurgitation severity changes and improvement in NYHA classification are described in This is the first study that reports acute hemodynamic changes after MitraClip therapy solely for functional mitral regurgitation without influence of general anaesthesia and measured invasively by right heart catheterisation. The principal findings are as follows: mitral clipping resulted in rapid increase of CI by 66% with concomitant reduction in SVRI by 50% and mean PCWP by 42% present already on first postoperative day. None of our patients experienced deterioration of haemodynamic stability despite the fact that most subjects had poor ventricular function (preprocedure LV ejection fraction was 34 ± 12%).n = 107). The principal difference is in patient population, especially with respect to MR aetiology . Importantly, all hemodynamic data were obtained only under general anaesthesia with well-known effect on haemodynamic situation. Very similar results were reported by Gaemperli et al. [Our results are in agreement with previously published work by Siegel et al.  from theTo the best of our knowledge, our work is the first to invasively measure and describe the acute haemodynamic changes after MitraClip implantation in selected and homogenous cohort of patients with functional MR and severely depressed LV systolic function while carefully avoiding the confounding influence of general anaesthesia on haemodynamic situation. There is no deterioration including severe decompensated group of MR patients and in fact improvement in hemodynamic situation very quickly after this procedure. In summary, increase in forward cardiac output after MitraClip implantation indicates that the beneficial effect of end-diastolic unloading outweighs the negative effect of afterload increase. This is in contrast to well established belief  that elimination of MR leads to decrease of LV systolic function and low cardiac output state.The important question remains: will the measured favourable hemodynamic parameters be translated to improved clinical outcomes? There is evidence that patients with increased CO and decreased filling pressures after MitraClip procedure have positive effect on LV remodelling with decrease in LV size and increase in LV ejection fraction . These hThis is in agreement with our experience; there was significant improvement in patient symptoms expressed by NYHA class after 1 month and significant improvement of LV ejection fraction.The main limitation of our work is the small number of studied subjects. This project was initiated only after our centre gained initial experience with this new method to avoid the influence of learning curve. We had carefully conducted all measurements but we are not able to account for possible changes in patient hydration. This is difficult as the patient is fasting prior to the procedure; the fluids administered during the procedure include usually poorly quantified catheter flushing and some patients do receive diuretic therapy after the procedure. Another technical issue might be linked to the use of thermodilution measurement; this may be affected by the presence of severe tricuspid regurgitation. However, only 4 of our patients had severe TR. In the postprocedure measurements, the usually present left-to-right shunting from iatrogenic atrial septal defect can underestimate CO.The reduction of mitral regurgitation using percutaneous MitraClip device results in a quick improvement of cardiac output state in patients with functional mitral regurgitation. These results are independent of the influence of general anaesthesia. None of our patients developed low cardiac output state. Our results support the idea that significant part of low cardiac output state after cardiac surgery for mitral regurgitation is due to surgery related factors rather than being due to sudden increase in afterload. These findings may have important implications for the use of percutaneous MitraClip device in older patients with severe MR and poor LV function who have a high risk of developing postoperative low cardiac output state.


Our aim was to evaluate changes in LV systolic and diastolic function in breast cancer patients early after anthracycline chemotherapy, and to identify predisposing factors.140 patients were assessed by detailed echocardiography before and within seven days post treatment. LV ejection fraction (LVEF), global longitudinal strain (GLS), strain rate and radial and circumferential strain were assessed. Additionally, left atrial volumes and LV diastolic parameters were evaluated. LVEF although reduced after treatment, remained within the normal range . Triplane GLS was significantly reduced after treatment . Subclinical LV dysfunction (>11% reduction in GLS compared to before therapy) occurred in 22% (29/135). Impaired diastolic function grade significantly increased from 46% to 57% (p<0.001) after treatment. Furthermore, diastolic dysfunction was more common in the subgroup group with reduced systolic GLS compared to those without changes in GLS . No risk factors or clinical parameters were associated with the development of subclinical LV dysfunction; however the percentage change in early diastolic strain rate and the E velocity were independent predictors of >11% reduction in GLS.Twenty two percent of patients had subclinical LV dysfunction by GLS, whilst none had cardiotoxicity defined by LVEF, demonstrating that GLS is more sensitive for detection of subclinical LV systolic dysfunction immediately after anthracycline therapy. Diastolic dysfunction increased, particularly in the group with reduced GLS, demonstrating the close pathophysiological relationship between systolic and diastolic function. Anthracyclines are the cornerstone in breast cancer chemotherapy  with doxEchocardiography is the foundation for monitoring cardiotoxicity . HistoriWhile early changes in systolic function have been described, only limited studies with small sample sizes have assessed the effect of anthracycline chemotherapy on LV diastolic function, and particularly the relationship between systolic and diastolic function in this setting. Diastolic dysfunction may precede systolic dysfunction providing an early marker of cardiotoxicity and development of heart failure with relatively preserved systolic function.We evaluated LV systolic and diastolic function in a large single centre cohort of chemotherapy naïve breast cancer patients before anthracycline treatment and within seven days after treatment, to evaluate myocardial dysfunction in a larger cohort than previously published reports. The main aim of this study was to evaluate and characterise the cardiotoxic effects of anthracyclines by the use of strain analysis and traditional echocardiographic measures. We also sought to examine segmental LV function and to identify clinical and echocardiographic predictors for the development of subclinical LV dysfunction.Study approval was obtained from the Committees for Human Research at Sydney West Area Health Service and the University of Sydney; all subjects provided written informed consent. 151 consecutive patients with histologically confirmed breast cancer were prospectively recruited. Anthracycline chemotherapy, either doxorubicin or epirubicin, was administered (4 to 6 cycles) as determined by the treating oncologist. No patients were receiving trastuzumab therapy at the time of this study. 35 patients went on to be treated with trastuzumab after the conclusion of this study. All patients underwent detailed clinical evaluation including cardiovascular history and risk factors , cardioactive medications, family history, height, weight and blood pressure. Blood tests  were performed before and after completion of anthracycline chemotherapy. Exclusion criteria included previous chemotherapy or radiation treatment, coronary artery disease, more than mild valvular disease, history of atrial or ventricular arrhythmias, an LVEF <50%, previous cardiac surgery or implanted devices.All participants underwent a comprehensive transthoracic echocardiogram, according to established laboratory practice . Optimised imaging of the left ventricle (LV) was performed and all measurements were averaged over three consecutive cardiac cycles and offline analysis was performed using Echopac PC 6.1.0. . Baseline echocardiograms were performed at least one week prior to the commencement of anthracycline chemotherapy. Follow-up echocardiograms were performed within 7 days of completion of anthracycline chemotherapy (12 to 18 weeks following the baseline study) and prior to commencement of trastuzumab or thoracic radiation. Eleven patients were excluded due to inadequate image quality following left breast surgery; the remaining 140 patients were included in the analysis. All echocardiograms were performed with the patient in the left lateral position and images were obtained from the parasternal, apical and subcostal views.LV volumes were measured from the apical 4 and 2-chamber views using the modified Simpson’s biplane method of discs, and LVEF was calculated . Cardiac2D strain analysis was used to measure global and regional longitudinal systolic strain from the apical four, two and three chamber views  were measured using the biplane area-length method. Phasic LA volumes including passive, conduit and active volumes and fractions were also calculated . LA reseTransmitral inflow was obtained using pulsed wave Doppler. The peak velocity in early diastole (E wave velocity) and the peak velocity in late diastole (A wave velocity) and the E/A ratio were measured. The downward slope of the early diastolic E wave velocity was measured to obtain the deceleration time . The act2). The severest form of diastolic dysfunction is restrictive filling and was present if E/A ratio was >2 and / or deceleration time was < 140 ms [LV diastolic dysfunction was stratified into four grades according to the ASE guidelines based on the E’ velocity, E/E’ ratio, E/A ratio, deceleration time and pulmonary vein flow as normal, impaired relaxation, pseudo normal filling or restrictive . Normal < 140 ms .All continuous variables are expressed as a mean ± SD and categorical variables as a percentage. Paired t-tests were used to compare parameters before and after anthracycline therapy. Subgroup analysis was performed using unpaired t-tests. Non-parametric variables were examined by Chi square analysis. Pearson correlations were used to examine associations between continuous parameters. Multivariate analysis was performed by logistic regression backward stepwise likelihood ratio. Inter- and intra-observer variability of LVEF, triplane GLS and systolic strain rate were assessed on fifteen randomly selected patients by intraclass correlation coefficient. Data were analysed using SPSS version 21 , and considered significant if p < 0.05.2) and 31/140 (24%) epirubicin . Cardiovascular risk factors and cardioactive medications are listed in A total of 140 prospectively recruited patients were included in the final analysis; 99/140 (76%) received doxorubicin (419 ± 67 mg/mHaemoglobin was significantly reduced after anthracycline therapy (p<0.001), whilst estimated glomerular filtration rate (p = 0.53) and creatinine (p = 0.24) remained unchanged .Follow up echocardiograms were performed 95 ± 18 days following the baseline study, within 7 days of completion of anthracycline chemotherapy. No patient developed significant valvular / pericardial disease or heart failure early after anthracycline chemotherapy.Clinical and echocardiographic parameters before and after anthracycline chemotherapy are listed in Subclinical LV dysfunction, defined as >11% reduction in triplane GLS, occurred in 29 patients (22%). Subclinical LV dysfunction was not associated with any cardiovascular risk factors , clinical characteristics , type of anthracycline therapy or dose. The incidence of subclinical LV dysfunction by GLS did not correlate with the percentage change in LVEF (p = 0.05). In the sub group with >11% reduction in GLS, there was no significant difference in LV end diastolic volume (p = 0.98) or LV end systolic volume (p = 0.37) compared to before treatment. The incidence of subclinical LV dysfunction was not associated with the percentage change in global circumferential (p = 0.39) or radial strain (p = 0.57).Nine patients were receiving either an angiotensin converting enzyme inhibitor  or a beta blocker  prior to chemotherapy. There were no significant differences in LVEF, GLS, radial or circumferential strain before or after anthracyclines between this group and those not receiving these medications.Patients receiving doxorubicin had similar LVEF compared to epirubicin after therapy . Additionally there was no significant difference in triplane GLS  after therapy between the drug types. 21% (21/102) in the doxorubicin group and 24% (8/33) in the epirubicin group had subclinical LV dysfunction by triplane GLS (p = 0.63).In the group with subclinical LV dysfunction by GLS all 18 regional segments had significantly reduced strain after therapy , while uThe intra and inter-observer intraclass coefficients for LVEF were 0.77 and 0.84, for triplane GLS were 0.95 and 0.86, for systolic strain rate were 0.83 and 0.70,LA volumes did not change post anthracycline therapy . HoweverDiastolic parameters are listed in In the present study we evaluated LV systolic function prior to, and within seven days of completing anthracycline based chemotherapy using LVEF and strain analysis, in 140 consecutive breast cancer patients. The principal findings of the study were; 1) longitudinal and circumferential strain were significantly reduced after anthracycline therapy, despite clinically insignificant changes in LVEF, 2) LV subclinical dysfunction, defined as a >11% reduction in GLS, occurred in 22% of the cohort, 3) reductions in global strain were induced equally by doxorubicin and epirubicin, 4) in patients with >11% reduction in GLS, greater segmental strain reduction was evident and 5) increased occurrence of diastolic dysfunction occurred with subclinical systolic dysfunction.This study includes a relatively large number of breast cancer patients treated only with anthracycline chemotherapy, and confirms the occurrence of subclinical LV systolic dysfunction post therapy as reported previously , 16, 17.Negishi et al demonstrated that a reduction of >11% in GLS was predictive of the longer term reduction in LVEF and cardiotoxicity  in patieDoxorubicin and epirubicin are the most frequently used anthracyclines in breast cancer regimens . Both agThe incidence of myocardial damage after anthracycline chemotherapy may be enhanced by smoking , preexisEarly identification of subclinical LV dysfunction is important as this patient subgroup requires close monitoring and enables early initiation of cardioprotective agents. Treatment with an angiotensin receptor blocker (candesartan) prior to anthracycline, trastuzumab and radiotherapy was demonstrated to alleviate reduced LVEF , in the Diastolic dysfunction has been previously reported following anthracycline chemotherapy , 30–33, LV diastolic grade was worse in the current cohort after anthracycline chemotherapy. Importantly, diastolic dysfunction was more prevalent in the sub group with >11% reduction in GLS, demonstrating the close association between systolic and diastolic function. In fact, the only predictors of >11% reduction in GLS was early diastolic strain rate and the mitral peak E velocity. Altered early LV relaxation resulted in augmented active atrial contraction with increased atrial fraction and late diastolic strain rate, to compensate for the decreased volume transfer during early diastole. These changes, however, were only evident by Doppler parameters and not atrial volume measurements, which are more reflective of the chronicity of LV diastolic dysfunction. The monitoring of diastolic function is of particular importance as alterations in diastolic function with relatively preserved systolic function can also result in heart failure.This single-centre study (n = 140) is significantly larger than previous single-centre studies. Due to cost constraints cardiac biomarkers could not be obtained in the majority of the cohort. The study was limited by the short duration of patient follow-up, and therefore the longer term impact of early reduction in GLS is uncertain; longer term follow up is ongoing to determine the significance of these early observations. Another imaging modality may have provided additional information about LV systolic function; the use of MRI was beyond the scope of the current study. 3D echocardiography, contrast imaging and stress testing were not performed in the current cohort. Image acquisition and measurements were performed using equipment from a single vendor (GE); therefore values are not comparable with non-GE machines . MeasureSubclinical LV dysfunction by GLS was observed in 22% of patients. There was an increase in prevalence of LV diastolic dysfunction in the subgroup with >11% reduction in GLS. No clinical risk factors were predictive of subclinical LV dysfunction, thus emphasizing the need for all patients to be monitored for deterioration in both systolic and diastolic function following anthracycline treatment. Longer term follow up is needed and is presently ongoing to determine the clinical importance of these early findings.S1 File(XLSX)Click here for additional data file.


We sought to determine the prognostic value of qualitative and quantitative analysis obtained by real-time myocardial perfusion echocardiography (RTMPE) in patients with known or suspected coronary artery disease (CAD).Quantification of myocardial blood flow reserve (MBFR) in patients with CAD using RTMPE has been demonstrated to further improve accuracy over the analysis of wall motion (WM) and qualitative analysis of myocardial perfusion (QMP).From March 2003 to December 2008, we prospectively studied 168 patients with normal left ventricular function (LVF) who underwent dobutamine stress RTMPE. The replenishment velocity reserve (β) and MBFR were derived from RTMPE. Acute coronary events were: cardiac death, myocardial infarction and unstable angina with need for urgent coronary revascularization.During a median follow-up of 34 months (5 days to 6.9 years), 17 acute coronary events occurred. Abnormal β reserve in ≥2 coronary territories was the only independent predictor of events hazard ratio (HR) = 21, 95% CI = 4.5–99; p<0.001). Both, abnormal β reserve and MBFR added significant incremental value in predicting events over qualitative analysis of WM and MP . When coronary angiographic data was added to the multivariate analysis model, β reserve remained the only predictor of events with HR of 21.0 (95% CI = 4.5–99); p<0.001.Quantitative dobutamine stress RTMPE provides incremental prognostic information over clinical variables, qualitative analysis of WM and MP, and coronary angiography in predicting acute coronary events. Coronary artery disease (CAD) remains the foremost important cause of death worldwide. Preventing early deaths and the late consequences of myocardial infarction (MI) by a cost effective non-ionizing technique seems to be a reasonable part for the solution of this complex issue to our modern society .In order to non-invasively detect CAD in patients with normal left ventricular function (LVF), avoiding unnecessary coronary angiography, stress echocardiography has been utilized successfully for many years. However, the spatial extent and severity of induced ischemia are important factors with regard to prognosis and, unfortunately, wall motion (WM) analysis by stress echocardiography does not accurately represent these factors –4.Real-time myocardial perfusion echocardiography (RTMPE) has been demonstrated a useful technique for quantification of myocardial perfusion (MP) and determination of myocardial blood flow reserve (MBFR) –10. ProgWe sought to determine whether MBFR using dobutamine stress may add incremental prognostic value over conventional analysis of WM and MP in patients with known or suspected CAD and normal LVF.We prospectively studied 176 patients with known or suspected CAD who were referred for coronary angiography and underwent dobutamine-stress RTMPE. Inclusion criteria were: age ≥18 years, normal LVF (ejection fraction ≥50%). Exclusion criteria were previous coronary bypass graft surgery, unstable angina (UA), severe valvular disease, uncontrolled hypertension, ventricular arrhythmias, allergy to contrast, intracardiac shunt, pregnancy and breast-feeding. Median interval between RTMPE and coronary angiography was 17 days (1–52 days). The study protocol was approved by the ethical committee of Heart Institute—University of São Paulo Medical School and all patients gave written informed consent to participate. Quantitative coronary angiography was performed using a computerized system II CAAS . A significant stenosis was defined as one which reduced luminal diameter by ≥50%. Patients were divided into those with normal coronary arteries, those with a significant lesion in 1 coronary artery territory (CAT) and those with lesions in ≥2 CAT.-1. min-1. This was followed by increasing doses of 10, 20, 30 to a maximal dose of 40μg. Kg-1. min-1 in 3 minute stages. Atropine (up to 2 mg) was injected during the 20μg. Kg-1. min-1 infusion, if heart rate was <100 beats/min [A complete resting two-dimensional echocardiogram was performed, with special attention for the assessment of global and segmental left ventricular systolic function. Baseline left ventricular ejection fraction was calculated using modified Simpson’s rule  and the eats/min . Peak stEnd points of dobutamine stress were achievement of target heart rate , maximal dobutamine/atropine doses, development of severe or extensive WM abnormalities or intolerable side effects. Blood pressure and cardiac rhythm were continuously monitored prior, during and 20 minutes after dobutamine infusion. Twelve-lead electrocardiograms were obtained at baseline and at each 3-minute intervals during dobutamine infusion, and at any time at the operating physician’s discretion. The dobutamine stress was considered diagnostic if the target heart rate and/or inducible abnormalities were detected by qualitative analysis of WM or MP. The tests were considered nondiagnostic if the patients failed to achieve the target heart rate without inducible WM or MP abnormalities.th segment was also scored for WM when an abnormality was observed at the very edge of the left ventricular apex. A test was considered positive for WM analysis if new segmental WM abnormalities were present in one or more segments [Qualitative analysis of segmental myocardial contraction was based on visual assessment of myocardial thickening during optimal cavity contrast enhancement and was graded according to a scoring system as follows: 1-normal, 2-hypokinesis, 3-akinesis and 4-dyskinesis. In order to maintain linearity with the MP analysis, the 17segments . In the Off-line image analysis for quantification was performed with a commercially available software . Regions of interest were traced manually within the 17 segments of myocardium and in the adjacent left ventricular cavity. Myocardial plateau  and adjacent left ventricular plateau  signal intensities, and signal intensity exchange rate (ß/s)–that is proportional to myocardial blood flow velocity—were calculated automatically by the software. Normalized myocardial acoustic intensity (An) was defined as the ratio of AM divided by ALV, representing the relative myocardial blood volume  , 21, 22.The cutt-off values of ß reserve and MBFR that represent the points of best performance for accurately diagnose angiographically coronary obstruction have been previously reported in our laboratory and were used in this study to differentiate normal and abnormal ß reserve and MBFR . The cutCoronary angiography was performed by Judkins technique by femoral puncture using an equipment Integris H-3000  with digital processing of images. After the acquisition, the images were stored in an optical disc format or DICOM . Quantitative coronary angiography was performed using a computerized system II CAAS . A significant stenosis was defined as one which reduced luminal diameter by ≥ 50%. Patients were divided into those with normal coronary arteries, those with a significant lesion in one arterial territory and those with lesions in two or more arterial territories.Follow-up was obtained by review of the patient´s hospital chart, electronic records and telephone interview with the patients. Acute coronary events were defined as cardiac death, nonfatal myocardial infarction, and refractory or unstable angina requiring coronary revascularization during the same hospitalization. Cardiac death was defined as death associated with known or suspected myocardial infarction, life-threatening arrhythmia, or pulmonary edema. Sudden unexpected death occurring without another explanation was included as cardiac death. Nonfatal myocardial infarction was defined by means of a serial increase in cardiac specific enzymes and/or development of new ECG changes. Patients who underwent elective coronary revascularizations during the follow-up period for other indications  were censored at the time of procedure, since the stress echocardiography results could have influenced the decision to revascularization. The date of an event was used to establish the time of follow-up, or in the absence of an event, the date of the last interview or review of medical records were used to determine it.Data were expressed as mean value ± standard deviation for continuous variables, and absolute (n) or relative (%) frequencies for discrete variables. Data normality was tested by D’Agostino-Pearson Omnibus test. Discrete variables were analyzed by Chi-square test or Fischer exact test, if necessary. Continuous variables among groups were analyzed by Student’s t-test or ANOVA  and Mann-Whitney or Kruskal-Wallis . The Kaplan-Meier curves were used to estimate the distribution of time to the events. The Cox model was used to estimate the hazard ratio (HR) of events for each variable. The differences between the event curves were compared with the log-rank test. Clinical variables inserted in the model were age, male sex, ≥ risk factors for CAD , stable angina, previous myocardial infarction and previous percutaneous coronary intervention. Parameters derived from dobutamine stress RTMPE included WM , qualitative MP , β reserve  and MBFR . Multivariate predictors of events were determined by the Cox proportional-hazards model. The incremental value of RTMPE information was assessed in 3 modeling steps. The first step consisted of fitting a multivariate model of qualitative analysis of WM only . Qualitative analysis of MP by RTMPE was then added to this model , followed by quantitative analysis of MP using β reserve (< 2.0 or ≥ 2.0) or MBFR (< 2.6 or ≥ 2.6). The significance of adding additional variables to previous modeling steps was based on the change in model-based likelihood statistics, with degrees of freedom equal to the number of additional variables. Intraobserver variability was assessed using the coefficient of variation and intraclass correlation coefficient. A two-tailed p value < 0.05 was considered statistically significant. Statistical tests were performed using software SPSS 13.0 for Windows .Among the 176 patients initially considered for enrollment, 8 patients were excluded because they did not complete dobutamine-stress RTMPE. The final study population was constituted by 168 patients. There were 91 men (54%), and the mean age was 58±8.7 years. Risk factors for CAD were diabetes mellitus in 63 (37.5%), systemic hypertension in 148 (88%), hypercholesterolemia in 140 (83.3%), and cigarette smoking in 35 (20.8%) patients. One hundred twenty-seven (76%) patients were taking beta-blockers, 119 (70.8%) statins, 144 (85.7%) aspirin and 43 (25.6%) calcium channel blockers. Twenty-eight (17%) patients had a history of a previous myocardial infarction and 17 (10%) had previous percutaneous interventions.The contrast agent Definity was used in 94 (56%) patients and PESDA in 74 (44%). The mean maximal dose of dobutamine during the stress test was 30±6 μg/Kg/min. Atropine was infused in 158 (94%) patients. The mean percentage of maximal predicted heart rate achieved at peak stress was heart rate increased from 64±11 beats/min at baseline to 81±16 beats/min at peak stress (p<0.001). There were no significant changes from baseline to peak stress in systolic blood pressure  and diastolic blood pressure . The stress test was accomplished without serious complications in all patients. No myocardial infarction or death occurred either during or immediately after dobutamine stress.Follow-up data were available in all patients. Patients were followed for a median of 34 months . A total of 17 (10.1%) patients had acute coronary events during the follow-up . Acute coronary events occurred at a median of 9 months  after the dobutamine stress RTMPE. A total of 21 patients underwent elective coronary revascularizations during follow-up period for other reasons than unstable angina and the follow-up was censured at the time of procedure. Patients without events were followed-up for a minimum of 3 months.Resting WM was abnormal in at least one coronary artery territory in 28 patients (17%). All patients had normal resting ejection fraction. Inducible WM abnormalities were observed in 56 (33%) patients while MP abnormalities by qualitative analysis were observed in 85 (51%) patients. Patients with abnormal WM during dobutamine stress RTMPE had a higher proportion of acute coronary events (p = 0.019) during follow-up. Patients with abnormal MP by qualitative analysis also had a higher proportion of acute coronary events (p = 0.013) during follow-up. The Kaplan-Meier survival curves according to the results of WM and qualitative analysis of MP are illustrated in Quantitative analysis of RTMPE was performed by coronary artery territories and by patients. The coefficient of variation for β reserve was 10.7%, with intraclass correlation coefficient of 0.94 . The coefficient of variation for MBFR reserve was 11.6%, with intraclass correlation coefficient of 0.97 . Among the 168 patients, 28 (16.7%) had abnormal β reserve in only one coronary artery territory and 66 (39%) in ≥2 territories. The characteristics of patients according to β results are presented in Among the 168 studied patients, 31 (18%) had coronary stenosis in only 1 territory and 55 (33%) had abnormal coronary artery in ≥2 territories. Kaplan-Meier survival curves according to the results of MBFR are illustrated in Sequential Cox regression models were fit to test the incremental value of quantitative parameters of RTMPE over WM and qualitative analysis of MP . The preThe presence abnormal β reserve in ≥2 territories increased the likelihood of acute coronary events among all variables -myocardial perfusion imaging in 51 patients with known or suggested CAD . The autIn the present study, we studied a selected population of patients with preserved ventricular function, and also found that qualitative analysis of MP was predictive of acute coronary events. However, quantitative analysis of MP was even more predictive, having independent predictive value over all clinical, echocardiographic, and angiographic variables. Previously, our group found a cut-off value for β reserve of 2.0 was optimal for detecting angiographically significant CAD , and herIn multivariate analysis, abnormal β reserve in two or more coronary territories was the best independent predictor of events. This finding defines that a larger spatial distribution of reduced MBFR identifies patients at higher risk. This is consistent with qualitative data already established in the literature for other stress echocardiographic modalities , 34, 35 Since patients in this study were already undergoing coronary angiography, we may have selected those at the greatest clinical risk. However, nearly half of the patients still did not have an angiographically significant coronary stenosis. Furthermore, patients who had “compelling anatomy” and had percutaneous revascularization at the time of the diagnostic angiogram were also excluded. This resulted in an actual event rate of only 10% over the approximate three year follow-up period. Therefore, the population studied was similar to what would be expected for patients presenting for stress echocardiography. This study was a single center study, with a vast experience in performing RTMPE. Although this may have affected the results of the qualitative assessments of MP, it probably had little impact on the quantitative assessments of MBFR. The quantitative assessments of perfusion are time consuming, and require proper placement of the regions of interest, but less prone to subjectivity or operator experience. Nonetheless, multicenter trials will be required to determine the ability of quantitative assessments of MBFR to predict outcome during dobutamine stress echocardiography in a broader setting. A concerted effort of the different ultrasound manufacturers is also needed, to standardize the quantitative measurements, and assist in developing normal databases as well as a more eficiente, used-friendly quantification software.Quantification of myocardial blood flow velocity reserve during dobutamine stress RTMPE is an independent predictor of acute coronary events in patients with known or suspected CAD with preserved left ventricular function, and provides additional prognostic information over clinical variables, qualitative analysis of WM and MP, and coronary angiography data. Quantitative parameters identify a subgroup of individuals at a higher risk of cardiac events, especially when the abnormal flow reserve involves more than one coronary artery territories.S1 Table(PDF)Click here for additional data file.


Biventricular failure is associated with high in‐hospital mortality. Limited data regarding the efficacy of biventricular Impella axial flow catheters (BiPella) support for biventricular failure exist. The aim of this study was to explore the clinical utility of percutaneously delivered BiPella as a novel acute mechanical support strategy for patients with cardiogenic shock complicated by biventricular failure.CP (n=11), or Impella 2.5 (n=1). All patients received the Impella RP for right ventricular (RV) support. BiPella use was recorded in the setting of acute myocardial infarction (n=11), advanced heart failure (n=7), and myocarditis (n=2). Mean flows achieved were 3.4±1.2 and 3.5±0.5 for left ventricular and RV devices, respectively. Total in‐hospital mortality was 50%. No intraprocedural mortality was observed. Major complications included limb ischemia (n=1), hemolysis (n=6), and Thrombolysis in Myocardial Infarction major bleeding (n=7). Compared with nonsurvivors, survivors were younger, had a lower number of inotropes or vasopressors used before BiPella, and were more likely to have both devices implanted simultaneously during the same procedure. Compared with nonsurvivors, survivors had lower pulmonary artery pressures and RV stroke work index before BiPella. Indices of RV afterload were quantified for 14 subjects. Among these patients, nonsurvivors had higher pulmonary vascular resistance , effective pulmonary artery elastance , and lower pulmonary artery compliance .We retrospectively analyzed data from 20 patients receiving BiPella for biventricular failure from 5 tertiary‐care hospitals in the United States. Left ventricular support was achieved with an Impella 5.0 (n=8), Impella RV device implantation and lower RV afterload may be associated with better outcomes with BiPella. Future prospective studies of BiPella for cardiogenic shock are required.This is the largest, retrospective analysis of BiPella for cardiogenic shock. BiPella is feasible, reduces cardiac filling pressures and improves cardiac output across a range of causes for cardiogenic shock. Simultaneous left ventricular and  Biventricular support with 2 axial flow Impella catheters (BiPella) improves the hemodynamic profile of patients with cardiogenic shock.Compared to staged implantation, simultaneous deployment of left ventricular and right ventricular Impella support devices is associated with improved survival.Indices of increased right ventricular afterload in cardiogenic shock are associated with higher in‐hospital mortality among BiPella recipients.Nonsurgical deployment of left ventricular and right ventricular Impella catheters for biventricular circulatory support is clinically feasible with no intraprocedural mortality or device failure.Careful evaluation of hemodynamic parameters, including indices of right ventricular afterload, is important for guidance of device selection. Algorithms are required to guide optimal device utilization.Cardiogenic shock (CS) is associated with high in‐hospital mortality.We retrospectively analyzed the records of 20 patients with BiVF who received BiPella support between 2013 and 2016 from 5 tertiary care institutions. BiPella support was defined as any combination of percutaneously delivered Impella 5.0, Impella CP, or Impella 2.5 for LV support and Impella RP for RV support. The decision to implant BiPella for biventricular support was operator dependent. Patients receiving VA‐ECMO, TandemHeart, or surgically implanted ventricular assist devices (VADs) before BiPella initiation were excluded. All subjects received standard clinical care for BiVF during their index hospitalization. The institutional review board for each participating institution approved this study. Subject informed consent was waived.Demographic information, hemodynamic and echocardiographic data, laboratory parameters, and outcome data were recorded by investigators at each institution. Implantation sequence and timing as well as flow settings were dictated by operators at each institution without a uniform, predefined protocol or algorithm. To explore the hemodynamic effect of BiPella, pulmonary artery (PA) catheter indices acquired within 24 hours before and after implantation of both LV and RV support devices were compared. In all 20 subjects, both pre‐ and post‐BiPella hemodynamics were available. Cardiac filling pressures, cardiac output (CO) by the Fick method, and established indices of RV function including the right atrial (RA) pressure/pulmonary capillary wedge pressure (PCWP) ratio, the pulmonary artery pulsatility ratio (PA pulse pressure/RA pressure), and RV stroke work index ([mean PA−RA]/stroke volume index). In 14 of 20 subjects, complete hemodynamic data were available for analysis of indices of RV afterload including: pulmonary vascular resistance ; PA compliance (stroke volume/[PA systolic pressure−PA diastolic pressure]); PA elastance ([PA systolic pressure]/stroke volume); and effective PA elastance ([PA systolic pressure−PCWP]/stroke volume). Clinical outcomes including in‐hospital mortality, time to device activation, and device‐associated complications occurring during or within 24 hours of right‐ or left‐sided device implantation or removal were studied. Thrombolysis in Myocardial Infarction major bleeding was defined as either intracranial hemorrhage, clinical signs of hemorrhage associated with a drop in hemoglobin, or fatal bleeding that resulted with in death within 7 days of device implantation.t test for continuous variables and Fisher's exact test for categorical variables. Within a survival cohort, pair‐wise t tests were used for pre‐ versus postcomparisons whereas data between survival cohorts were analyzed using 2‐sample equal variance t tests. All statistical analysis was performed using GraphPad Prism software . A P value of <0.05 denoted significant difference.Data are expressed as mean±95% confidence interval (95% CI) for continuous variables. Differences between groups and conditions were compared by Student P=0.02), were younger , and required fewer vasopressors and/or inotropes before device implantation . Total duration of BiPella support was 5.3  and 4.9  days for nonsurvivors and survivors, respectively (P=0.81). No difference in laboratory parameters was observed between groups , acutely decompensated heart failure , and myocarditis . All acute myocardial infarction patients underwent emergent and successful percutaneous coronary revascularization. Left‐sided support was provided with an Impella 5.0 (n=8), Impella CP (n=11), or Impella 2.5 (n=1). Impella 5.0 was implanted by the axillary route in 7 of 8 patients. All other patients received Impella 5.0, CP, or 2.5 devices by a femoral artery. All patients received an Impella RP by a femoral vein for RV support. Mean flows achieved were 3.4±1.2 and 3.5±0.5 for LV and RV devices, respectively. No intraprocedural mortality was observed with any device implantation. No device failure requiring explant was reported. Major complications included limb ischemia , hemolysis , and Thrombolysis in Myocardial Infarction major bleeding .2), elevated RA pressure , elevated PCWP , high RA/PCWP ratios , low pulmonary artery pulsatility ratios , and low LV cardiac power output . Compared with survivors, nonsurvivors had higher baseline PA systolic pressures , PA diastolic pressures , mean PA pressures , and RV stroke work index .All 20 patients had a cardiac index <2.2 despite inotropic or vasopressor support  and index , PA systolic pressures , PA diastolic pressures , and mean PA pressures . CO  and index  were also increased, but these values were not statistically significant. Among survivors, BiPella reduced RA pressure , PA diastolic pressures , PCWP , and increased both CO  with a trend toward increased cardiac index .Among all 20 patients, Bipella reduced cardiac filling pressures Table . BipellaP<0.001), PA elastance , effective PA elastance , and lower PA compliance  and the PVR/PA compliance ratio was higher among nonsurvivors (6.2; 95% CI, 4.2–8.2 versus 1.1; 95% CI, 0.2–1.7; nonsurvivors versus survivors; P<0.001; Figure Based on these data, in‐hospital mortality appeared to be associated with pulmonary hypertension before BiPella implantation. To explore this further, we next analyzed hemodynamic determinants of RV afterload. Compared with survivors, nonsurvivors had higher PVR (6.8; 95% CI, 5.5–8.1 versus 1.9; 95% CI, 0.8–3.0; This report is the largest, retrospective analysis of patients receiving 2 percutaneously delivered microaxial flow Impella catheters for LV and RV support in the setting of CS complicated by biventricular failure. The central finding of this report is that BiPella is clinically feasible and associated with reduced cardiac filling pressures and improved CO across a range of causes for CS. Overall in‐hospital mortality remained high for this critically ill population with severely depressed LV function, massively elevated biventricular filling pressures, reduced RV function, evidence of multiorgan impairment, and elevated lactate levels. Demographic characteristics favoring survival among Bipella recipients for CS included lower age, reduced vasopressor and inotrope requirement before BiPella support, and implantation of LV and RV devices during the same procedure. A closer look at the hemodynamic condition of patients in this study identified that survivors had lower PA pressures compared with nonsurvivors. Based on this observation, we studied indices of RV afterload and identified that high PVR, high effective PA elastance, and lower PA compliance were associated with in‐hospital mortality. These findings identify, for the first time, that BiPella support is feasible, improves hemodynamic conditions in CS, and may be more effective in patients with low PA pressures and reduced RV afterload.The use of surgical VADs has increased exponentially with over 13 000 implants between 2006 and 2014.Our findings have several major implications for the field of mechanical circulatory support. First, we identified that nonsurgical, rapid deployment of LV and RV Impella catheters for biventricular circulatory support is clinically feasible across multiple centers without intraprocedural mortality or device failure. This represents a significant advance in our ability to provide hemodynamic support for patients with cardiogenic shock. Past biventricular support approaches include use of extracorporeal centrifugal flow pumps and include the TandemHeart device or VA‐ECMO.Second, consistent with reports from the surgical VAD literature, we identified that higher preprocedural vasopressor and/or inotropic requirements and increased lactate levels are associated with higher mortality. Both of these indices may be considered markers of a more‐prolonged duration of cardiogenic shock leading to metabolic failure. At this stage, acute mechanical circulatory support may be insufficient to improve survival. These findings highlight the importance of early identification and referral for acute mechanical circulatory support in patients with cardiogenic shock.Third, we identified that, among BiPella recipients, in‐hospital mortality is associated with elevated PA pressures and that, compared with survivors, nonsurvivors also had a higher RV stroke work index before BiPella implantation. These observations suggest that these patients may not have had biventricular failure, but rather had CS attributed to LV failure with secondary pulmonary hypertension and subsequent biventricular congestion. The nonsurvivor cohort may therefore not have benefited from implantation of a biventricular support device. Recent data suggest that elevated left‐sided filling pressures may serve as an “amplifier” of RV afterload by reducing PA compliance and increasing PVR.Limitations of our study include the small number of patients studied, which limited our ability to perform subgroup analyses. Furthermore, the retrospective nature of the analysis limited our ability to rigorously identify predictors of outcomes associated with BiPella therapy. Additionally, this was a multicenter study in which indications for BiPella implantation varied between institutions. The combinations of left‐ and right‐sided support devices also differed between patients and may have had effects on outcomes. Future studies with larger cohorts of patients are required.In conclusion, use of acute mechanical circulatory support devices for cardiogenic shock is growing. The ability to now provide biventricular circulatory support using 2 microaxial flow Impella catheters opens many new possibilities for the treatment of CS and advanced heart failure. Furthermore, the availability of these powerful tools mandates us all to become more familiar with advanced hemodynamics, especially around biventricular interactions and the right ventricular‐pulmonary arterial axis. Findings from this analysis may support the development of future treatment algorithms and prospective studies evaluating the use of BiPella in patients with acute myocardial infarction, acutely decompensated heart failure, pulmonary hypertension, or as a bridge to durable VAD therapy.Dr Kapur receives research funding from Maquet Inc, Cardiac Assist Inc, Abiomed Inc, St Jude Inc, and Boston Scientific Inc and speaker/consultant honoraria from Maquet Inc, Abiomed Inc, St. Jude Inc, and Heartware Inc.


In addition, a vascular occluder was placed around the left main coronary artery, and stimulating electrodes were secured onto the left ventricle. A single precisely timed electrical pulse (5 msec pulse width and 2.5 V) to the left ventricle arriving 13.9 ± 1.1 msec after the R‐wave, caused ventricular tachycardia occurring 24.9 ± 0.9 msec after the R‐wave. Importantly, a second precisely timed electrical pulse arriving 18.8 ± 0.5 msec after the first stimulus blocked the induction of ventricular tachycardia caused by the earlier stimulus. On an alternate day, the susceptibility to sustained ventricular tachycardia produced by 3.5 min of occlusion and reperfusion of the coronary artery was determined in conscious mice by use of the vascular occluder. Reperfusion resulted in ventricular tachycardia in all six mice. A precisely timed pulse within the protective period prevented ventricular tachycardia in all mice.Early pioneering investigators discovered, in anesthetized dogs, a protective period within the cardiac cycle. The protective period was a time within the cardiac cycle when a precisely timed stimulus prevented the initiation of ventricular fibrillation caused by an earlier stimulus. Thus, in addition to the susceptible period of repolarization discussed by Wiggers and Wegria , there is also a nearby protective period. This report describes a protective period within the cardiac cycle of conscious mice when a precisely timed stimulus prevented the initiation of ventricular tachycardia caused by an earlier stimulus. In addition, we tested the hypothesis that this precisely timed pulse within the protective period prevents reperfusion‐induced ventricular tachyarrhythmias in conscious mice. Mice ( The use of electrical currents to restore homeostasis is an emerging field. As examples, cardiac pacemakers and defibrillators restore cardiac rhythms, deep‐brain stimulation improves motor control for individuals living with Parkinson's disease, sacral nerve stimulation improves bladder control in individuals living with spinal cord injury, and vagal nerve stimulation is useful for individuals living with heart failure, epilepsy, and rheumatoid arthritis.Electrical impulses have also been used to prevent cardiac rhythm disorders , a strain frequently utilized in transgenic studies  and prepared for aseptic surgery. Additional pentobarbital  was administered if the mice responded to tail pinch.A left thoracotomy through the second intercostal space exposed the heart, and Teflon‐coated stainless steel wires were secured onto the surface of the left ventricle as previously described in mice  and following stimulation in the protective period (recovery). An alpha level of 0.05 was used to determine statistical significance.A sampling frequency of 4 kHz was used for all physiological recordings, and data were expressed as means ± SE. A one‐way analysis of variance with repeated measures was used to compare the arterial pressure and heart rate responses before stimulation in the vulnerable period (prestimulation), during the stimulation within the vulnerable period causing ventricular tachycardia (ventricular tachycardia), and following the cessation of ventricular tachycardia (recovery). A Holm–Sidak post hoc analysis was used to isolate group differences. A Student's paired Finally, box and whisker plots of the vulnerable and protective zones, arterial pressure and heart rate before the stimulus (which caused ventricular tachycardia) and during and after ventricular tachycardia as well as before the stimulus (which did not cause tachycardia), and following the stimulus were generated to display the variation in the data. The central box represents the values from the first and third quartiles (25–75 percentile). The vertical lines (whiskers) denote minimum and maximum values. The bold center line in each box plot represents the median value.The vulnerable zone VZ, Fig.  was a peThe timing of the pulse within the vulnerable zone to cause ventricular tachycardia was critical. For example, a pulse arriving early within the refractory period failed to evoke a cardiac response Fig.  panel A.A protective zone PZ, Fig.  was a peThe electrical pulse within the vulnerable zone significantly increased heart rate from 462 ± 37 to 762 ± 30 bpm. The ventricular tachycardia was associated with a significantly reduced arterial pressure from 105 ± 5 to 88 ± 7 mmHg. The data distribution of arterial pressure and heart before the stimulus (Prestimulus), during the stimulus within the vulnerable period causing ventricular tachycardia, and following the cessation of ventricular tachycardia (recovery) is presented as box and whisker plots  or heart rate (529 ± 60 vs. 534 ± 46 bpm). The intensity and duration of each electrical impulse within the protective zone that prevented ventricular tachycardia were 0.5 V and 5 msec duration, respectively. The data distribution of arterial pressure and heart rate before the stimulus (Prestimulus) and after the stimulus in the protective zone (recovery) is presented as box and whisker plots  declare(s) that there is no conflict of interest.